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(11) | EP 2 419 432 B1 |
(12) | EUROPEAN PATENT SPECIFICATION |
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(54) |
PYRIMIDINE COMPOUNDS, THEIR USE AS MTOR KINASE AND PI3 KINASE INHIBITORS, AND THEIR SYNTHESES PYRIMIDINVERBINDUNGEN, DEREN VERWENDUNG ALS MTOR-KINASE- UND PI3-KINASE-INHIBITOREN UND DEREN SYNTHESE COMPOSÉS DE PYRIMIDINE, LEUR UTILISATION COMME INHIBITEURS DE LA MTOR KINASE ET DE LA PI3 KINASE ET LEURS PROCÉDÉS DE SYNTHÈSE |
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Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). |
FIELD OF THE INVENTION
BACKGROUND OF THE INVENTION
SUMMARY OF THE INVENTION
DETAILED DESCRIPTION OF THE INVENTION
(i) C1-C6alkyl- optionally substituted with halogen,
(ii) (C1-C6alkoxy)carbonyl-,
(iii) (C1-C6alkyl)amido-,
(iv) (C1-C6alkyl)carboxyamido-,
(v) (C1-C6alkyl)carboxyl-,
(vi) C1-C6alkoxy-,
(vii) H2N-,
(viii) (C1-C6alkyl)amino-,
(ix) di(C1-C6alkyl)amino-,
(x) hydroxyl,
(xi) H2NC(O)-,
(xii) HO2C-,
(xiii) and -NO2;
wherein any two hydrogen atoms on the same carbon atom of the C3-C8cycloalkyl- ring can be replaced by an oxygen atom to form an oxo (=O) substituent,(i) HO2C-,
(ii) C1-C6hydroxylalkyl-,
(iii) R12R13NC(O)-,
(iv) and (C1-C6alkoxy)carbonyl-;
1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea;
1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea; and
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phenyl}urea.
1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea;
2-hydroxyethyl {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}carbamate;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea;
1-ethyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea;
1-cyclopropyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea;
1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-[4-(hydroxymethyl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea;
2-hydroxyethyl {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}carbamate;
1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}urea;
1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-3-methylurea;
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-3-pyridin-4-ylurea;
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-1-ethyl-3-pyridin-4-ylurea;
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-1-ethyl-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
bis(2-hydroxyethyl) {[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}biscarbamate;
N',N"'-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis(1-methylurea);
N',N"'-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis(1-ethylurea);
N',N"'-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis(1-cyclopropylurea);
N,N"-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis(3-pyridin-3-ylurea);
N,N"-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis(3-pyridin-4-ylurea);
N',N"'-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis{1-[4-(4-methylpiperazin-1-yl)phenyl]urea};
4,4'-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]bis(4,1-phenylenecarbamoylimino)}dibenzamide;
1-methyl-3-{4-[4-(1-methylethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}urea;
1-cyclopropyl-3-{4-[4-(1-methylethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}urea;
1-{4-[4-(1-methylethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[4-(1-methylethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-methyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea;
1-cyclopropyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea;
1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
N∼3∼,N∼3∼-dimethyl-N-(4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-{4-[(pyridin-3-ylcarbamoyl)amino]phenyl}pyrimidin-5-yl)-beta-alaninamide;
1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl}urea;
1-cyclopropyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl}urea;
2-hydroxyethyl {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl}carbamate;
1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl}urea;
tert-butyl methyl(4-{[(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)carbamoyl]amino}benzyl)carbamate;
1-methyl-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea;
1-ethyl-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea;
1-cyclopropyl-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea;
1-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)-3-phenylurea;
1-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)-3-pyridin-3-ylurea;
1-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea;
1-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)3-(4-piperazin-1-ylphenyl)urea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea;
1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea; and
1-{4-[(methylamino)methyl]phenyl}-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea.
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-pyridin-4-ylurea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]urea;
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea;
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea;
1-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}urea;
1-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea;
1-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]urea;
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-pyridin-3-ylurea;
1-[4-(5-chloro-4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-pyridin-3-ylurea;
1-[4-(5-chloro-4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}urea;
1-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}urea;
1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}urea;
1-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}urea;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}urea;
1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}urea;
1-{4-[4-(diethylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[4-(diethylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-(4-{4-[(1-methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[4-(pyrrolidin-1-ylmethyl)phenyl]urea;
1-(4-{4-[(1-methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-3-ylurea;
1-{4-[(dimethylamino)methyl]phenyl}-3-(4-{4-[(1-methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea;
1-(4-{4-[(1-methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[4-(2-pyrrolidin-1-ylethoxy)phenyl]urea;
1-(4-{4-[(dimethylamino)methyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-3-ylurea;
1-(4-{4-[(dimethylamino)methyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-methylurea;
1-(4-{4-[(dimethylamino)methyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-ethylurea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-cyclopropylurea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-phenylurea;
1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea;
1-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea;
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea;
1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea;
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]urea;
1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]urea;
1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea;
1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)urea;
1-(4-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-(4-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea;
1-{4-[(dimethylamino)methyl]phenyl}-3-(4-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea;
1-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyimidin-2-yl}phenyl)-3-pyridin-4-ylurea ;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea;
1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea;
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-3-ylurea;
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea;
N,N-dimethyl-4-{[(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)carbamoyl]amino}benzamide;
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea;
1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea; and
1-(4-{4-[(dimethylamino)methyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-methylurea.
1-[4-(2,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phenyl]-3-methylurea;
1-[4-(2,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phenyl]-3-pyridin-4-ylurea;
1-[4-(2,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea; and
1-cyclopropyl-3-[4-(2,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phenyl]urea.
4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]aniline;
4-[4-chloro-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]aniline;
4-[2-chloro-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-4-yl]aniline;
8,8'-[2-(4-nitrophenyl)pyrimidine-4,6-diyl]bis(3-oxa-8-azabicyclo[3.2.1]octane);
4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)aniline;
4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}aniline;
4-(5-chloro-4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)aniline;
9-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-3,7-dioxa-9-azabicyclo[3.3.1]nonane;
6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-N-isopropyl-2-(4-nitrophenyl)pyrimidin-4-amine;
2-(4-aminophenyl)-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-N-isopropylpyrimidin-4-amine;
6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(4-nitrophenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine;
2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine;
6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(2-(methylsulfonyl)ethyl)-2-(4-nitrophenyl)pyrimidin-4-amine;
2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(2-(methylsulfonyl)ethyl)pyrimidin-4-amine;
6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N,N-diethyl-2-(4-nitrophenyl)pyrimidin-4-amine;
2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N,N-diethylpyrimidin-4-amine;
4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)aniline;
8-[6-(3,6-dihydro-2H-pyran-4-yl)-2-(4-nitrophenyl)pyrimidin-4-yl]-3-oxa-8-azabicyclo[3.2.1]octane; and
4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]aniline.
DEFINITIONS
EXAMPLES
SYNTHETIC METHODS
Scheme 1:
3-(2-Chloro-pyrimidin-4-yl)-8-oxa-3-aza-bicyclo[3.2.1]octane (3):
Scheme 2:
General conditions for Suzuki coupling (formation of 6):
Illustrative example for Suzuki coupling:
4-[4-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]aniline:
General conditions for urea or carbamate formation (conversion of 6 into 7):
Illustrative example for urea or carbamate formation (conversion of 6 into 7):
2-Hydroxyethyl {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}carbamate:
1-Methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}urea
1-{4-[4-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea
Scheme 3:
3-(2,6-Dichloro-pyrimidin-4-yl)-8-oxa-3-aza-bicyclo[3.2.1]octane (9):
Scheme 4:
4-[2-Chloro-6-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-4-yl]-phenylamine (11) and 4-[4-chloro-6-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-2-yl]-phenylamine (12):
Scheme 5:
3-[6-Chloro-2-(4-nitro-phenyl)-pyrimidin-4-yl]-8-oxa-3-aza-bicyclo[3.2.1]octane (13), 3-[2-chloro-6-(4-nitro-phenyl)-pyrimidin-4-yl]-8-oxa-3-aza-bicyclo[3.2.1]octane (14) and 3-[2,6-bis-(4-nitro-phenyl)-pyrimidin-4-yl]-8-oxa-3-aza-bicyclo[3.2.1]octane (15):
Scheme 6:
3-(6-Chloro-2-iodo-pyrimidin-4-yl)-8-oxa-3-aza-bicyclo[3.2.1]octane (16):
3-[6-Chloro-2-(4-nitro-phenyl)-pyrimidin-4-yl]-8-oxa-3-aza-bicyclo[3.2.1]octane (13)
Scheme 7:
Isopropyl-[2-(4-nitro-phenyl)-6-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-4-yl]-amine (17):
[2-(4-Amino-phenyl)-6-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-4-yl]-isopropyl-amine (18):
1-Methyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea
1-Cyclopropyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea
1-(4-{4-[(1-Methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea
1-(4-{4-[(1-Methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-y}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
Scheme 8:
4-[4-Isopropoxy-6-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-pyrimidin-2-yl]-phenylamine (19):
1-Methyl-3-{4-[4-(1-methylethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}urea
1-Cyclopropyl-3-{4-[4-(1-methylethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}urea
1-{4-[4-(1-Methylethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea
1-{4-[4-(1-Methylethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
Scheme 9:
3,3'-(2-(4-Nitrophenyl)pyrimidine-4,6-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane) (20):
4-(4,6-Di(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)aniline (21):
1-[4-(4,6-Di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-3-methylurea
1-[4-(4,6-Di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-3-pyridin-4-ylurea
1-[4-(4,6-Di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
1-[4-(4,6-Di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-1-ethyl-3-pyridin-4-ylurea
1-[4-(4,6-Di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-1-ethyl-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
Scheme 10:
3,3'-(6-(4-Nitrophenyl)pyrimidine-2,4-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane) (22):
4-(2,6-Di(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-4-yl)aniline (23):
1-[4-(2,6-Di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phenyl]-3-methylurea
1-[4-(2,6-Di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phenyl]-3-pyridin-4-ylurea
1-[4-(2,6-Di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phenyl]-3-[4-(4-1-yl)phenyl]urea
1-Cyclopropyl-3-[4-(2,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phenyl]urea
Scheme 11:
3-[2,6-Bis-(4-aminophenyl)-pyrimidin-4-yl]-8-oxa-3-aza-bicyclo[3.2.1]octane (24):
Formation of urea or carbamate (25) from 3-[2,6-Bis-(4-aminophenyl)-pyrimidin-4-yl]-8-oxa-3-aza-bicyclo[3.2.1]octane (24):
Bis(2-hydroxyethyl){[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}biscarbamate
N',N"'-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis(1-methylurea)
N',N"'-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis(1-ethylurea)
N',N"'-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis(1-cyclopropylurea)
N,N"-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis(3-pyridin-3-ylurea)
N,N"-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis(3-pyridin-4-ylurea)
N',N"'-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis{1-[4-(4-methylpiperazin-1-yl)phenyl]urea}
4,4'-{[6-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]bis(4,1-phenylenecarbamoylimino)}dibenzamide
Scheme 12:
4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloropyrimidin-2-ol (26):
Scheme 13
4,6-Di(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-2-ol (27):
3,3'-(2-Chloropyrimidine-4,6-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane) (28):
Scheme 14:
4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(isopropylamino)pyrimidin-2-ol (29):
6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-chloro-N-isopropylpyrimidin-4-amine (30):
Scheme 15:
4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-isopropoxypyrimidin-2-ol (31):
3-(2-Chloro-6-isopropoxypyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (32):
Scheme 16:
8-(2,6-Dichloropyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (34):
8-(6-Chloro-2-iodopyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (35):
8-(6-Chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (36):
8,8'-(2-(4-Nitrophenyl)pyrimidine-4,6-diyl)bis(3-oxa-8-azabicyclo[3.2.1]octane) (37):
4-(4,6-Di(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-2-yl)aniline (38):
1-[4-(4,6-Di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-pyridin-4-ylurea
1-{4-[2-(Dimethylamino)ethoxy]phenyl}-3-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]urea
1-[4-(4,6-Di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
1-[4-(4,6-Di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea
1-[4-(4,6-Di-3-oxa-8-azabicydo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea
Scheme 17:
2,4-Dichloro-6-phenylpyrimidine (39):
3-(2-Chloro-6-phenylpyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (40):
4-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-phenylpyrimidin-2-yl)aniline (41):
Formation of urea or carbamate compounds from 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-phenylpyrimidin-2-yl)aniline (41):
1-Methyl-3{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea:
2-Hydroxyethyl{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}carbamate :
1-[4-(4-Methylpiperazin-1-yl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea
1-Ethyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea
1-Cyclopropyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea
1-{4-[4-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yi)-6-phenylpyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea
1-[4-(Hydroxymethyl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea
1-{4-[2-(Dimethylamino)ethoxy]phenyl}-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea
Scheme 18:
3-(2-Chloro-6-(methylsulfonylmethyl)pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (43):
4-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimidin-2-yl)aniline (44):
Formation of urea or carbamate compounds from 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimidin-2-yl)aniline (44):
1-(4-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimidin-2-yl)phenyl)-3-methylurea
1-(4-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimidin-2-yl)phenyl)-3-ethylurea
11-(4-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimidin-2-yl)phenyl)-3-cyclopropylurea
1-(4-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimidin-2-yl)phenyl)-3-phenylurea
1-(4-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimidin-2-yl)phenyl)-3-(pyridin-3-yl)urea
1-(4-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimidin-2-yl)phenyl)-3-(pyridin-4-yl)urea
1-(4-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimidin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea
1-(4-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimidin-2-yl)phenyl)-3-(4-(piperazin-1-yl)phenyl)urea :
1-(4-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimidin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea
1-(4-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimidin-2-yl)phenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)urea
Tert-butyl 4-(3-(4-(4-{8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimidin-2-yl)phenyl)ureido)benzyl(methyl)carbamate
1-(4-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(methylsulfonylmethyl)pyrimidin-2-yl)phenyl)-3-(4-((methylamino)methyl)phenyl)urea:
Scheme 19
3-(2,6-Dichloro-5-nitropyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (46)
6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-chloro-N-isopropyl-5-nitropyrimidin-4-amine (47)
6-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-chloro-N4-isopropylpyrimidine-4,5-diamine3-(dimethylamino)propanoate (48)
N-(4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-2-chloro-6-(isopropylamino)pyrimidin-5-yl)-3-(dimethylamino)propanamide (49)
Scheme 20:
1-(Pyridin-3-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (52)
N-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(isopropylamino)-2-(4-(3-pyridin-3-ylureido)phenyl)pyrimidin-5-yl)-3-(dimethylamino)propanamide (53)
Scheme 21:
4-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloropyrimidin-2-yltrifluoromethanesulfonate (54):
3-[6-Chloro-2-(4-nitro-phenyl)-pyrimidin-4-yl]-8-oxa-3-aza-bicyclo[3.2.1]octane (13):
Scheme 22:
4-Nitrobenzimidamide, HCl (57):
2-(4-Nitrophenyl)pyrimidine-4,6-diol (58):
4,6-Dichloro-2-(4-nitrophenyl)pyrimidine (59):
8-(6-Chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane (36):
6-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-isopropyl-2-(4-nitrophenyl)pyrimidin-4-amine (60):
2-(4-Aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-isopropylpyrimidin-4-amine (61):
1-{4-[4-(Isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea
1-{4-[2-(Dimethylamino)ethoxy]phenyl}-3-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}urea
1-{4-[4-(Isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
1-{4-[4-(Isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-(4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea
1-{4-[4-(Isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]urea
Scheme 23
2,4-Dichloro-6-(trifluoromethyl)pyrimidine (62):
3-(2-Chloro-6-trifluoromethyl-pyrimidin-4-yl)-8-oxa-3-aza-bicyclo[3.2.1]octane (63):
4-[4-(8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-6-trifluoromethyl-pyrimidin-2-yl]-phenylamine (64):
1-Methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl}urea:
1-Cyclopropyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl}urea
2-Hydroxyethyl{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl}carbamate:
1-{4-[4-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea, trifluoroacetate salt
1-[4-(4-Methylpiperazin-1-yl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl}urea trifluoroacetate salt:
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-pyridin-3-ylurea
Scheme 26
8,8'-(2,5-dichloropyrimidine-4,6-diyl)bis(3-oxa-8-azabicyclo[3.2.1]octane):
4-(5-chloro-4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)aniline:
1-[4-(5-chloro-4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-pyridin-3-ylurea:
1-[4-(5-chloro-4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea:
Scheme 27
9-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-3,7-dioxa-9-azabicyclo[3.3.1]nonane:
6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-N-isopropyl-2-(4-nitrophenyl)pyrimidin-4-amine:
2-(4-aminophenyl)-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-N-isopropylpyrimidin-4-amine:
1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea:
1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea:
1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea:
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phenyl}urea:
Scheme 28
6-chloro-2-(4-nitrophenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine and 6-chloro-N,N-diethyl-2-(4-nitrophenyl)pyrimidin-4-amine:
Scheme 29
6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(4-nitrophenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine:
2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine:
Alternative procedure for the preparation of 2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine:
Step 1:
Step 2:
1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea:
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}urea:
1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea:
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}urea:
1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}urea:
Scheme 30
6-chloro-N-(2-(methylsulfonyl)ethyl)-2-(4-nitrophenyl)pyrimidin-4-amine:
6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(2-(methylsulfonyl)ethyl)-2-(4-nitrophenyl)pyrimidin-4-amine:
2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(2-(methylsulfonyl)ethyl)pyrimidin-4-amine:
1-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea:
1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}urea:
1-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea:
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}urea:
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}urea:
1-(4-{4-[(1-methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[4-(pyrrolidin-1-ylmethyl)phenyl]urea:
1-(4-{4-[(1-methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-3-ylurea:
1-{4-[(dimethylamino)methyl]phenyl}-3-(4-{4-[(1-methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea:
1-(4-{4-[(1-methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[4-(2-pyrrolidin-1-ylethoxy)phenyl]urea:
Scheme 31
6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N,N-diethyl-2-(4-nitrophenyl)pyrimidin-4-amine:
2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N,N-diethylpyrimidin-4-amine:
1-{4-[4-(diethylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea:
1-{4-[4-(diethylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea:
Scheme 32
8-(2-chloro-6-(chloromethyl)pyrimidin-4-yl)-3-oxa-8-azabicyclo[3.2.1]octane:
1-(6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-chloropyrimidin-4-yl)-N,N-dimethylmethanamine:
Scheme 33
1-(pyridin-3-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea:
1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea:
1-(4-(4-methylpiperazin-1-yl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea:
1-(4-(2-(dimethylamino)ethoxy)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea:
1-(4-((dimethylamino)methyl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea:
1-phenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea:
Scheme 34
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-(pyridin-3-yl)urea:
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-cyclopropylurea:
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea:
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea:
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea:
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-phenylurea:
Scheme 35 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)aniline:
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-methylurea:
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-ethylurea:
Scheme 36
8-[6-(3,6-dihydro-2H-pyran-4-yl)-2-(4-nitrophenyl)pyrimidin-4-yl]-3-oxa-8-azabicyclo[3.2.1]octane (74):
4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]aniline (75):
General procedure for formation of carbamoyl or urea compounds from 4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]aniline (75):
1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea:
1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea:
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea:
1-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea:
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea:
1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea:
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea:
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]urea
1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea
1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea
1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]urea
1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea
1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)urea
1-(4-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-(4-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea
1-{4-[(dimethylamino)methyl]phenyl}-3-(4-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea
1-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea
1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-3-ylurea
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea
N,N-dimethyl-4-{[(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)carbamoyl]amino}benzamide
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea
1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea
1-(4-{4-[(dimethylamino)methyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-methylurea
BIOLOGICAL EVALUATION
PI3K-alpha and PI3K-gamma Fluorescence Polarization Assay Protocols
mTOR Enzyme Assay
In vitro cell growth assay
Name | mTOR IC50 (nM) | PI3Kα IC50 (nM) | PI3Kγ IC50 (nM) | LNCAP IC50 (µM) | MDA IC50 (µM) |
1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea | 22 | 953 | 0.51 | 2 | |
2-hydroxyethyl {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}carbamate | 21.5 | 452 | 0.6 | 5.5 | |
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea | 17.5 | 2430 | 0.078 | 0.27 | |
1-ethyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea | 11 | 2048 | 0.45 | 1.9 | |
1-cyclopropyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea | 19.5 | 3678 | 1 | 5 | |
1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea | 5.6 | 229 | 0.29 | 0.39 | |
1-[4-(hydroxymethyl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea | 2.9 | 102 | 0.056 | 0.13 | |
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea | 19 | 141 | 0.12 | 0.3 | |
2-hydroxyethyl {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}carbamate | 165 | 5070 | 4 | 24 | |
1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}urea | 132.5 | 1843 | 2.5 | 10.5 | |
1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea | 14.5 | 224 | 0.18 | 0.65 | |
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-3-methylurea | 7.05 | 1085 | 0.25 | 1 | |
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-3-pyridin-4-ylurea | 0.56 | 125 | 0.028 | 0.05 | |
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea | 2.55 | 328.5 | 0.0024 | 0.019 | |
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-1-ethyl-3-pyridin-4-ylurea | 200 | 2256 | 5.8 | 20 | |
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-1-ethyl-3-[4-(4-methylpiperazin-1-yl)phenyl]urea | 195 | 2438 | 2.8 | 7 | |
bis(2-hydroxyethyl){[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}biscarbamate | 9.4 | 5004 | 0.24 | 1.6 | |
N',N"'-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis(1-methylurea) | 2.8 | 990 | 1.2 | 1.1 | |
N',N"'-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis(1-ethylurea) | 1.85 | 1663 | 0.31 | 0.79 | |
N',N"'-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis(1-cyclopropylurea) | 4 | 2925 | 0.31 | 1.5 | |
N,N"-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis(3-pyridin-3-ylurea) | 2.8 | 101 | 0.18 | 0.38 | |
N,N"-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis(3-pyridin-4-ylurea) | 3.2 | 69.5 | 0.22 | 0.78 | |
N',N"'-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis{1-[4-(4-methylpiperazin-1-yl)phenyl]urea} | 2.15 | 1018 | 0.3 | 0.76 | |
4,4'-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]bis(4,1-phenylenecarbamoylimino)}dibenzamide | 0.58 | 44.5 | 0.041 | 0.045 | |
1-methyl-3-{4-[4-(1-methylethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}urea | 3 | 700 | 0.19 | 0.89 | |
1-cyclopropyl-3-{4-[4-(1-methylethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}urea | 4.45 | 7200 | 0.29 | 1.8 | |
1-{4-[4-(1-methylethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea | 1.35 | 264 | 0.023 | 0.18 | |
1-{4-[4-(1-methylethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea | 3.325 | 518.5 | 0.03 | 0.105 | |
1-methyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea | 12 | 810 | 0.5 | 2.1 | |
1-cyclopropyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea | 8.2 | 3623 | 0.7 | 4.2 | |
1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea | 0.785 | 140 | 0.051 | 0.31 | |
1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea | 4.175 | 211.5 | 0.0134 | 0.05 | |
N∼3∼,N∼3∼-dimethyl-N-(4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-{4-[(pyridin-3-ylcarbamoyl)amino]phenyl}pyrimidin-5-yl)-beta-alaninamide | 13500 | 5979 | 30 | 60 | |
1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl}urea | 11.5 | 1553 | 0.67 | 2.1 | |
1-cyclopropyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl}urea | 10.4 | 8159 | 0.45 | 3 | |
2-hydroxyethyl {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl}carbamate | 15.5 | 5158 | 0.95 | 4 | |
1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea | 2.45 | 280 | 0.05 | 0.25 | |
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl}urea | 11 | 440 | 0.05 | 0.19 | |
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-pyridin-4-ylurea | 0.655 | 954 | 0.003 | 0.019 | |
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]urea | 2.5 | 1542 | 0.004 | 0.009 | |
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea | 1.7 | 1136 | 0.0008 | 0.0008 | |
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea | 2.25 | 1952 | 0.0008 | 0.004 | |
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea | 0.94 | 129 | 0.0008 | 0.0008 | |
tert-butyl methyl(4-{[(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)carbamoyl]amino}benzyl)carbamate | 30 | 1933 | 0.21 | 0.47 | |
1-methyl-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea | 13.5 | 1727 | 2.05 | 3.3 | |
1-ethyl-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea | 5.75 | 1807 | 1 | 1.9 | |
1-cyclopropyl-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea | 5.7 | 4640 | 1 | 2.5 | |
1-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)-3-phenylurea | 3 | 172 | 0.0009 | 0.009 | |
1-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)-3-pyridin-3-ylurea | 1.02 | 341 | 0.195 | 0.17 | |
1-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea | 0.825 | 236 | 0.15 | 0.075 | |
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea | 2.95 | 343 | 0.015 | 0.03 | |
1-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)-3-(4-piperazin-1-ylphenyl)urea | 3 | 242 | 0.09 | 0.11 | |
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea | 5 | 405 | 0.09 | 0.165 | |
1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea | 4.05 | 520 | 0.08 | 0.14 | |
1-{4-[(methylamino)methyl]phenyl}-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea | 4.15 | 63.5 | 1.1 | 1.56 | |
1-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea | 1.4 | 2498 | 0.013 | 0.029 | |
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}urea | 3.6 | 2380 | 0.05 | 0.71 | |
1-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea | 2.7 | 1996 | 0.019 | 0.034 | |
1-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea | 3.2 | 3410 | 0.07 | 0.11 | |
1-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]urea | 4.2 | 3870 | 0.09 | 0.1 | |
1-[4-(2,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phenyl]-3-methylurea | 20.5 | 2488 | 1.6 | 4.2 | |
1-[4-(2,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phenyl]-3-pyridin-4-ylurea | 2.45 | 137 | 0.13 | 0.38 | |
1-[4-(2,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea | 9.55 | 588 | 0.04 | 0.16 | |
1-cyclopropyl-3-[4-(2,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phenyl]urea | 38.5 | 3931 | 0.8 | 6 | |
4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]aniline | 4000 | 6846 | 41 | 60 | |
4-[4-chloro-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]aniline | |||||
4-[2-chloro-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-4-yl]aniline | |||||
8,8'-[2-(4-nitrophenyl)pyrimidine-4,6-diyl]bis(3-oxa-8-azabicyclo[3.2.1]octane) | |||||
4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)aniline | |||||
4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}aniline | |||||
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-pyridin-3-ylurea | 0.58 | 1128 | 4487 | 0.8 | 5 |
1-[4-(5-chloro-4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-pyridin-3-ylurea | 0.655 | 922 | 932 | 48 | 220 |
1-[4-(5-chloro-4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea | 0.505 | 998 | 1016 | 65 | 210 |
1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea | 5 | 1521 | 9238 | 280 | 400 |
1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea | 17.5 | 3164 | 6872 | 600 | 1000 |
1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea | 14.5 | 1509 | 7889 | 280 | 320 |
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phenyl}urea | 16.5 | 1758 | 8629 | 420 | 600 |
1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea | 3.8 | 2012 | 11985 | 40 | 40 |
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}urea | 7.5 | 2262 | 9231 | 7 | 10 |
1-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea | 5 | 1639 | 10000 | 2000 | 800 |
1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}urea | 17.5 | 3982 | 10765 | 400 | 500 |
1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea | 3.3 | 2675 | 10000 | 50 | 160 |
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}urea | 7.6 | 1112 | 4537 | 30 | 48 |
1-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea | 4.05 | 1301 | 10781 | 1000 | 400 |
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}urea | 26 | 1859 | 10000 | 480 | 420 |
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}urea | 14.5 | 1840 | 10000 | 17 | 19 |
1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}urea | 6.3 | 931 | 2181 | 40 | 65 |
1-{4-[4-(diethylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea | 4.55 | 2411 | 1987 | ||
1-{4-[4-(diethylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea | 5.85 | 2914 | 3390 | 132 | 560 |
1-(4-{4-[(1-methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[4-(pyrrolidin-1-ylmethyl)phenyl]urea | 2.95 | 1093 | 3576 | 110 | 80 |
1-(4-{4-[(1-methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-3-ylurea | 1.1 | 4354 | 10000 | 45 | 100 |
1-{4-[(dimethylamino)methyl]phenyl}-3-(4-{4-[(1-methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea | 2.65 | 1186 | 3880 | 120 | 120 |
1-(4-{4-[(1-methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[4-(2-pyrrolidin-1-ylethoxy)phenyl]urea | 3.05 | 1324 | 4733 | 50 | 55 . |
1-(4-{4-[(dimethylamino)methyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-3-ylurea | 10.85 | 3163 | >10000 | 600 | 1000 |
1-(4-{4-[(dimethylamino)methyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-methylurea | 77 | 7996 | >10000 | 3600 | 7000 |
1-(4-{4-[(dimethylamino)methyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-ethylurea | 40 | 6243 | 12584 | 1100 | 3000 |
1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea | 0.320 | 2686 | 10000 | 0.004 | 0.2 |
1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea | 0.365 | 1784 | 7975 | 0.0008 | 0.004 |
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea | 0.855 | 1060 | 4728 | 0.0008 | 0.004 |
1-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea | 1.215 | 2589 | 10000 | 0.0008 | 0.004 |
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea | 0.440 | 230 | 3053 | 0.0008 | 0.0008 |
1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea | 0.295 | 353 | 3209 | 0.0008 | 0.0008 |
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea | 1.150 | 1462 | 7296 | 0.004 | 0.011 |
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea | 0.645 | 314 | 778 | 0.001 | 0.005 |
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea | 1.250 | 864 | 3502 | 0.0008 | 0.001 |
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]urea | 2.500 | 1096 | 2985 | 0.0035 | 0.008 |
1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea | 2.600 | 1344 | 5371 | 0.05 | 0.28 |
1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea | 4.400 | 1547 | 6437 | 0.03 | 0.13 |
1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]urea | 15.250 | 1694 | 15308 | 0.1 | 0.2 |
1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea | 3.550 | 180 | 1028 | 0.0008 | 0.0008 |
1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)urea | 2.700 | 293 | 915 | 0.0008 | 0.0008 |
1-(4-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea | 3.050 | 2809 | 10000 | 0.03 | 0.075 |
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-(4-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea | 9.750 | 1784 | 10000 | 0.01 | 0.018 |
1-{4-[(dimethylamino)methyl]phenyl}-3-(4-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea | 16.000 | 1244 | 10000 | 0.06 | 0.15 |
1-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea | 2.250 | 1889 | 7428 | 0.09 | 0.11 |
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea | 7.550 | 2094 | 8714 | 0.04 | 0.048 |
1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea | 9.900 | 1187 | 7592 | 0.18 | 0.19 |
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea | 12.000 | 2745 | 9468 | 0.12 | 0.13 |
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-3-ylurea | 0.770 | 1062 | 7474 | 0.02 | 0.08 |
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea | 1.200 | 1298 | 8480 | 0.006 | 0.012 |
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea | 1.550 | 853 | 6473 | 0.004 | 0.013 |
N,N-dimethyl-4-{[(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)carbamoyl]amino}benzamide | 0.440 | 108 | 1637 | 0.0008 | 0.0008 |
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea | 0.750 | 78 | 1130 | 0.0008 | 0.0008 |
1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea | 0.600 | 123 | 1203 | 0.0008 | 0.0008 |
1-(4-{4-[(dimethylamino)methyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-methylurea | 77.000 | 7996 | 10000 | 3.6 | 7 |
(a) H;
(b) C1-C6alkyl- optionally substituted with from 1 to 3 substituents independently selected from:
(i) C1-C6alkoxy-,
(ii) H2N-,
(iii) (C1-C6alkyl)amino-,
(iv) di(C1-C6alkyl)amino-,
(v) C6-C14aryl-,
(vi) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl-,
(vii) and C1-C9heteroaryl-;
(c) C1-C6alkoxy-;
(d) C1-C9heteroaryl- optionally substituted with from 1 to 3 substituents independently selected from:
(i) C1-C6alkyl- optionally substituted with H2N-,
(ii) heterocyclyl(C1-C6alkyl)-,
(iii) halogen,
(iv) hydroxyl,
(v) H2N-,
(vi) O2N-,
(vii) H2NSO2-,
(viii) HO2C-,
(ix) (C1-C6alkoxy)carbonyl-,
(x) (C1-C6alkoxy)C(O)NH-,
(xi) (C1-C6alkyl)amino-,
(xii) di(C1-C6alkyl)amino-,
(xiii) R10R11NC(O)-,
(xiv) R10O-,
(xv) R10R11N-,
(xvi) R10R11NS(O)2-,
(xvii) R10S(O)2NR11-,
(xviii) R10R11NC(O)NH-,
(xix) R10S-,
(xx) R10S(O)-,
(xxi) R10S(O)2-,
(xxii) R10C(O)-,
(xxiii) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl- or C1-C6hydroxylalkyl-,
(xxiv) C1-C6hydroxylalkyl-,
(xxv) and perfluoro(C1-C6)alkyl-;
(e) C1-C6hydroxylalkyl-;
(f) C1-C9heterocyclyl-;
(g) C6-C14aryl- optionally substituted with from 1 to 3 substituents independently selected from:
(i) C1-C6alkyl- optionally substituted with H2N-,
(ii) heterocyclyl(C1-C6alkyl)-,
(iii) halogen,
(iv) hydroxyl,
(v) H2N-,
(vi) O2N-,
(vii) H2NSO2-,
(viii) HO2C-,
(ix) (C1-C6alkoxy)carbonyl-,
(x) (C1-C6alkoxy)C(O)NH-,
(xi) (C1-C6alkyl)amino-,
(xii) di(C1-C6alkyl)amino-,
(xiii) R10R11NC(O)-,
(xiv) R10O-,
(xv) R10R11N-,
(xvi) R10R11NS(O)2-,
(xvii) R10S(O)2NR11-,
(xviii) R10R11NC(O)NH-,
(xix) R10S-,
(xx) R10S(O)-,
(xxi) R10S(O)2-,
(xxii) R10C(O)-,
(xxiii) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl- or C1-C6hydroxylalkyl-,
(xxiv) C1-C6hydroxylalkyl-,
(xxv) and perfluoro(C1-C6)alkyl-;
(h) or C3-C8cycloalkyl-;
R10 and R11 are each independently H, C1-C6alkoxy-, C1-C6alkyl-, C1-C6alkoxy(C2-C6alkylene)-, (C1-C6alkyl)amino-C2-C6alkylene-, di(C1-C6alkyl)amino-C2-C6alkylene-, C2-C6alkenyl, C2-C6alkynyl, C6-C14aryl-, (C6-C14aryl)alkyl-, C3-C8cycloalkyl-, C1-C9heteroaryl-, (C1-C9heteroaryl)alkyl-, C1-C9heterocyclyl- optionally substituted by C1-C6alkyl-, or heterocyclyl(C1-C6alkyl-);(a) H;
(b) C1-C6alkyl- optionally substituted with from 1 to 3 substituents independently selected from:
(i) C1-C8acyl-
(ii) C1-C6alkoxy- optionally substituted with -NH2,
(iii) (C1-C6alkoxy)carbonyl-,
(iv) H2N-,
(v) (C1-C6alkyl)amino-,
(vi) di(C1-C6alkyl)amino-,
(vii) (C1-C6alkyl)carboxyamido-, optionally substituted with
A) H2N-,
B) (C1-C6alkyl)amino-,
C) or di(C1-C6alkyl)amino-,
(viii) C6-C14aryl-,
(ix) C3-C8cycloalkyl-
(x) halogen,
(xi) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl-,
(xii) HO2C-,
(xiii) NC-,
(xiv) R10C(O)NR11-,
(xv) R10R11NC(O)-,
(xvi) and C1-C9heteroaryl-;
(c) C1-C6alkoxy-;
(d) C1-C9heteroaryl- optionally substituted with from 1 to 3 substituents independently selected from:
(i) C1-C6alkoxy- optionally substituted with
A) H2N-,
B) (C1-C6alkyl)amino-,
C) di(C1-C6alkyl)amino-,
D) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl-,
E) and hydroxyl,
(ii) (C1-C6alkoxy)carbonyl-,
(iii) (C1-C6alkoxy)C(O)NH-,
(iv) C1-C6alkyl- optionally substituted with
A) H2N-,
B) (C1-C6alkyl)amino-,
C) or di(C1-C6alkyl)amino-,
(v) (C1-C6alkyl)amino-,
(vi) di(C1-C6alkyl)amino-,
(vii) (C1-C6alkyl)amido- optionally substituted with
A) H2N-,
B) (C1-C6alkyl)amino-,
C) or di(C1-C6alkyl)amino-,
(viii) (C1-C6alkyl)carboxyamido-,
(ix) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl- or C1-C6hydroxylalkyl-,
(x) heterocyclyl(C1-C6alkyl)- optionally substituted by C1-C6alkyl-,
(xi) halogen,
(xii) hydroxyl,
(xiii) C1-C6hydroxylalkyl-,
(xiv) perfluoro(C1-C6)alkyl-,
(xv) H2N-,
(xvi) O2N-,
(xvii) H2NSO2-,
(xviii) HO2C-,
(xix) NC-,
(xx) R10R11NC(O)-,
(xxi) R10R11NNHC(O)-,
(xxii) R10O-,
(xxiii) R10R11N-,
(xxiv) R10R11NS(O)2-,
(xxv) R10S(O)2NR11-,
(xxvi) R10R11NC(O)NH-,
(xxvii) R10S-,
(xxviii) R10S(O)-,
(xxix) R10S(O)2-,
(xxx) and R10C(O)-;
(e) C1-C6hydroxylalkyl-;
(f) C1-C9heterocyclyl- optionally substituted with from 1 to 3 substituents independently selected from:
(i) C1-C6alkyl-,
(ii) heterocyclyl(C1-C6alkyl),
(iii) (C6-C14aryl)alkyl-,
(iv) C1-C8acyl-,
(v) (C1-C6alkoxy)carbonyl-,
(vi) (C1-C6alkyl)carboxyl- ,
(vii) halogen,
(viii) C1-C6haloalkyl-,
(ix) hydroxyl,
(x) C1-C6hydroxyalkyl-,
(xi) H2N-,
(xii) (C1-C6alkyl)amino-,
(xiii) di(C1-C6alkyl)amino-,
(xiv) HO2C-,
(xv) (C1-C6alkoxy)carbonyl-,
(xvi) (C1-C6alkyl)carboxyl-,
(xvii) (C1-C6alkyl)amido-,
(xviii) H2NC(O)-,
(xix) (C1-C6alkyl)carboxyamido-,
(xx) and -NO2;
(g) C6-C14aryl- optionally substituted with from 1 to 3 substituents independently selected from:
(i) C1-C6alkoxy- optionally substituted with
A) H2N-,
B) (C1-C6alkyl)amino-,
C) di(C1-C6alkyl)amino-,
D) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl-,
E) and hydroxyl,
(ii) (C1-C6alkoxy)carbonyl-,
(iii) (C1-C6alkoxy)C(O)NH-,
(iv) C1-C6alkyl- optionally substituted with
A) H2N-,
B) (C1-C6alkyl)amino-,
C) or di(C1-C6alkyl)amino-,
(v) (C1-C6alkyl)amino-,
(vi) di(C1-C6alkyl)amino-,
(vii) (C1-C6alkyl)amido- optionally substituted with
A) H2N-,
B) (C1-C6alkyl)amino-,
C) or di(C1-C6alkyl)amino-,
(viii) (C1-C6alkyl)carboxyamido-,
(ix) C1-C9heterocyclyl- optionally substituted by C1-C6alkyl- or C1-C6hydroxylalkyl-,
(x) heterocyclyl(C1-C6alkyl)- optionally substituted by C1-C6alkyl-,
(xi) halogen,
(xii) hydroxyl,
(xiii) C1-C6hydroxylalkyl-,
(xiv) perfluoro(C1-C6)alkyl-,
(xv) H2N-,
(xvi) O2N-,
(xvii) H2NSO2-,
(xviii) HO2C-,
(xix) NC-,
(xx) R10R11NC(O)-,
(xxi) R10R11NNHC(O)-,
(xxii) R10O-,
(xxiii) R10R11N-,
(xxiv) R10R11NS(O)2-,
(xxv) R10S(O)2NR11-,
(xxvi) R10R11NC(O)NH-,
(xxvii) R10S-,
(xxviii) R10S(O)-,
(xxix) R10S(O)2-,
(xxx) and R10C(O)-;
(h) and C3-C8cycloalkyl- optionally substituted with from 1 to 3 substituents independently selected from:
(i) C1-C6alkyl- optionally substituted with halogen,
(ii) (C1-C6alkoxy)carbonyl-,
(iii) (C1-C6alkyl)amido-,
(iv) (C1-C6alkyl)carboxyamido-,
(v) (C1-C6alkyl)carboxyl-,
(vi) C1-C6alkoxy-,
(vii) H2N-,
(viii) (C1-C6alkyl)amino-,
(ix) di(C1-C6alkyl)amino-,
(x) hydroxyl,
(xi) H2NC(O)-,
(xii) HO2C-,
(xiii) and -NO2;
wherein any two hydrogen atoms on the same carbon atom of the C3-C8cycloalkyl- ring can be replaced by an oxygen atom to form an oxo (=O) substituent,a) hydrogen;
b) C1-C8acyl-;
c) C1-C6alkyl-;
d) H2N- optionally substituted with C1-C9heterocycle,
e) (C1-C6alkyl)amino- optionally substituted with (C1-C6alkyl)SO2-,
f) di(C1-C6alkyl)amino- optionally substituted with (C1-C6alkyl)SO2-,
g) (C1-C6alkyl)amino-C1-C6alkylene-,
h) di(C1-C6alkyl)amino-C1-C6alkylene-,
i) amino(C1-C6alkyl)-;
j) C3-C8cycloalkyl-;
k) C6-C14aryl- optionally substituted with a substituent selected from:
i) HO2C-,
ii) C1-C6hydroxylalkyl-,
iii) R12R13NC(O)-,
iv) and (C1-C6alkoxy)carbonyl-;
l) C1-C9heterocycle optionally substituted with C1-C6alkyl-;
m) (C1-C9heteroaryl)alkyl-;
n) heterocyclyl(C1-C6alkyl)-;
o) (C6-C14aryl)alkyl-;
p) heterocyclyl(C1-C6alkyl);
q) (C1-C9heteroaryl)alkyl-;
r) (C6-C14aryl)alkyl-;
s) C1-C6hydroxylalkyl-;
t) C1-C6perfluoroalkyl-;
u) C1-C9heteroaryl- optionally substituted with a substituent selected from:
i) HO2C-,
ii) C1-C6hydroxylalkyl-,
iii) R12R13NC(O)-,
iv) and (C1-C6alkoxy)carbonyl-;
v) R3C(O)-N(R2)-Ar-;
w) R12R13NC(O)-;
x) R14OC(O)-;
y) or R14S(O)2-;
R5 is:a) hydrogen;
b) C1-C8acyl-;
c) C1-C6alkyl-;
d) amino(C1-C6alkyl)-;
e) C3-C8cycloalkyl-;
f) C6-C14aryl- optionally substituted with a substituent selected from:
i) HO2C-,
ii) C1-C6hydroxylalkyl-,
iii) R12R13NC(O)-,
iv) and (C1-C6alkoxy)carbonyl-;
g) halogen;
h) C1-C9heterocycle optionally substituted with C1-C6alkyl-;
i) (C1-C9heteroaryl)alkyl-;
j) heterocyclyl(C1-C6alkyl)-;
k) (C6-C14aryl)alkyl-;
l) heterocyclyl(C1-C6alkyl);
m) (C1-C9heteroaryl)alkyl-;
n) (C6-C14aryl)alkyl-;
o) C1-C6hydroxylalkyl-;
p) C1-C6perfluoroalkyl-;
q) C1-C9heteroaryl- optionally substituted with a substituent selected from:
i) HO2C-,
ii) C1-C6hydroxylalkyl-,
iii) R12R13NC(O)-,
iv) and (C1-C6alkoxy)carbonyl-;
r) R12R13NC(O)-;
s) R14OC(O)-;
t) or R14S(O)2-;
R12 and R13 are each independently H, C1-C6alkyl-, C3-C8cycloalkyl-, C6-C14aryl-, C1-C9heteroaryl-, (C1-C9heteroaryl)alkyl-, heterocyclyl(C1-C6alkyl)-, (C6-C14aryl)alkyl-, or C1-C9heterocyclyl- optionally substituted by C1-C6alkyl-;1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea;
1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phenyl}urea;
1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea;
2-hydroxyethyl {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}carbamate;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea;
1-ethyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea;
1-cyclopropyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea;
1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-[4-(hydroxymethyl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}urea;
2-hydroxyethyl {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}carbamate;
1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}urea;
1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-3-methylurea;
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-3-pyridin-4-ylurea;
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-1-ethyl-3-pyridin-4-ylurea;
1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-1-ethyl-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
bis(2-hydroxyethyl) {[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}biscarbamate;
N',N"'-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis(1-methylurea);
N',N"'-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis(1-ethylurea);
N',N"'-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis(1-cyclopropylurea);
N,N"-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis(3-pyridin-3-ylurea);
N,N"-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis(3-pyridin-4-ylurea);
N',N"'-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phenylene}bis{1-[4-(4-methylpiperazin-1-yl)phenyl]urea};
4,4'-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]bis(4,1-phenylenecarbamoylimino)}dibenzamide;
1-methyl-3-{4-[4-(1-methylethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}urea;
1-cyclopropyl-3-{4-[4-(1-methy)ethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}urea;
1-{4-[4-(1-methylethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[4-(1-methylethoxy)-6-(8-oxa-3-azabicyclo[3:2.1]oct-3-yl)pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-methyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea;
1-cyclopropyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea;
1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
N∼3∼,N∼3∼-dimethyl-N-(4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-{4-[(pyridin-3-ylcarbamoyl)amino]phenyl}pyrimidin-5-yl)-beta-alaninamide;
1-methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl}urea;
1-cyclopropyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl}urea;
2-hydroxyethyl {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl}carbamate;
1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluoromethyl)pyrimidin-2-yl]phenyl}urea;
tert-butyl methyl(4-{[(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)carbamoyl]amino}benzyl)carbamate;
1-methyl-3-(4-{4-[(methylsuffonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea;
1-ethyl-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea;
1-cyclopropyl-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea;
1-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)-3-phenylurea;
1-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)-3-pyridin-3-ylurea;
1-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea;
1-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)-3-(4-piperazin-1-ylphenyl)urea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea;
1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea;
1-{4-[(methylamino)methyl]phenyl}-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phenyl)urea;
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-pyridin-4-ylurea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]urea;
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea;
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea;
1-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}urea;
1-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea;
1-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]urea;
1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-pyridin-3-ylurea;
1-[4-(5-chloro-4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-pyridin-3-ylurea;
1-[4-(5-chloro-4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}urea;
1-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}urea;
1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}urea;
1-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}urea;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}urea;
1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}urea;
1-{4-[4-(diethylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-{4-[4-(diethylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-(4-{4-[(1-methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[4-(pyrrolidin-1-ylmethyl)phenyl]urea;
1-(4-{4-[(1-methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-3-ylurea;
1-{4-[(dimethylamino)methyl]phenyl}-3-(4-{4-[(1-methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea;
1-(4-{4-[(1-methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[4-(2-pyrrolidin-1-ylethoxy)phenyl]urea;
1-(4-{4-[(dimethylamino)methyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-3-ylurea;
1-(4-{4-[(dimethylamino)methyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-methylurea;
1-(4-{4-[(dimethylamino)methyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-ethylurea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl}-3-cyclopropylurea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)urea;
1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-phenylurea;
1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}-3-pyridin-3-ylurea;
1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-ylurea;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea;
1-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea;
1-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea;
1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}urea;
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]urea;
1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl)phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]urea;
1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea;
1-(4-{4-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)urea;
1-(4-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-(4-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea;
1-{4-[(dimethylamino)methyl]phenyl}-3-(4-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea;
1-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-4-ylurea;
1-[4-(4-methylpiperazin-1-yl)phenyl]-3-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea;
1-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-3-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea;
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-pyridin-3-ylurea;
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}urea;
1-{4-[2-(dimethylamino)ethoxy]phenyl}-3-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea;
N,N-dimethyl-4-{[(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)carbamoyl]amino}benzamide;
1-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}urea;
1-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)urea;
1-(4-{4-[(dimethylamino)methyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-3-methylurea;
1-[4-(2,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phenyl]-3-methylurea;
1-[4-(2,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phenyl]-3-pyridin-4-ylurea;
1-[4-(2,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]urea;
1-cyclopropyl-3-[4-(2,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phenyl]urea;
4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]aniline;
4-[4-chloro-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]aniline;
4-[2-chloro-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-4-yl]aniline;
8,8'-[2-(4-nitrophenyl)pyrimidine-4,6-diyl]bis(3-oxa-8-azabicyclo[3.2.1]octane);
4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)aniline;
4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}aniline;
4-(5-chloro-4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)aniline;
9-(6-chloro-2-(4-nitrophenyl)pyrimidin-4-yl)-3,7-dioxa-9-azabicyclo[3.3.1]nonane;
6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-N-isopropyl-2-(4-nitrophenyl)pyrimidin-4-amine;
2-(4-aminophenyl)-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-N-isopropylpyrimidin-4-amine;
6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(4-nitrophenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine;
2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine;
6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(2-(methylsulfonyl)ethyl)-2-(4-nitrophenyl)pyrimidin-4-amine;
2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(2-(methylsulfonyl)ethyl)pyrimidin-4-amine;
6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N,N-diethyl-2-(4-nitrophenyl)pyrimidin-4-amine;
2-(4-aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N,N-diethylpyrimidin-4-amine;
4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)aniline;
8-[6-(3,6-dihydro-2H-pyran-4-yl)-2-(4-nitrophenyl)pyrimidin-4-yl]-3-oxa-8-azabicyclo[3.2.1]octane; and
4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]aniline.
a) synthesizing a compound of Formula 68 when N(R2)H is present:
by reacting a pyrimidine compound of the formula 66:
with a dioxaborolan-2-yl compound 67:
to give 68 wherein the variables are as defined in claim 1;
b) further comprising, reacting compound 68 with an acylating agent R3C(O)X, wherein X is a leaving group and wherein R3 is as defined in claim 1 to give I:
R1 unabhängig für C1-C6-Alkyl-, C6-C14-Aryl-, C1-C9-Heteroaryl-, Halogen oder Hydroxyl steht;
p für 0, 1, 2, 3, oder 4 steht;
het für eine verbrückte C5-C9-Heterobicyclyl-Gruppe, enthaltend mindestens ein Sauerstoffatom, mindestens ein Stickstoffatom und optional zusätzliche Heteroatome, ausgewählt aus Sauerstoff, Schwefel und Stickstoff, steht, und mit der Pyrimidyl-Gruppe verbunden ist durch eines der Stickstoffatome;
eines von A für C-R5 steht und die anderen zwei für N stehen;
Ar für C6-C14-Aryl- oder C1-C9- Heteroaryl- steht, wobei das C6-C14-Aryl- oder C1-C9-Heteroaryl- optional substituiert ist mit 1 bis 4 Substituenten, die unabhängig von einander ausgewählt sind aus C1-C6-Alkyl-, Halogen, Halogenalkyl-, Hydroxyl, Hydroxyl(C1-C6-alkyl)-, H2N-, Aminoalkyl-, Di(C1-C6-alkyl)amino-, HO2C-, (C1-C6-Alkoxy)carbonyl-, (C1-C6-Alkyl)carboxyl-, Di(C1-C6-Alkyl)amido-, H2NC(O)-, (C1-C6-Alkyl)amido- und O2N-;
und wobei das C6-C14-Aryl- oder C1-C9-Heteroaryl- an den Pyrimidinkern gebunden ist durch ein Kohlenstoffatom des C6-C14-Aryl- oder C1-C9-Heteroaryl-;
R2 für H oder C1-C6-Alkyl- steht;
R3 für R6, R7R8N-, R9S-, oder R9O- steht;
R6 steht für:
(a) H;
(b) C1-C6-Alkyl- optional substituiert mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus:
(i) C1-C6-Alkoxy-,
(ii) H2N-,
(iii) (C1-C6-Alkyl)amino-,
(iv) Di(C1-C6-alkyl)amino-,
(v) C6-C14-Aryl-,
(vi) C1-C9-Heterocyclyl-, optional substituiert mit C1-C6-Alkyl-,
(vii) und C1-C9-Heteroaryl-;
(c) C1-C6-Alkoxy-;
(d) C1-C9-Heteroaryl-, optional substituiert mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus:
(i) C1-C6-Alkyl-, optional substituiert mit H2N-,
(ii) Heterocyclyl(C1-C6-alkyl)-,
(iii) Halogen,
(iv) Hydroxyl,
(v) H2N-,
(vi) O2N-,
(vii) H2NSO2-,
(viii) HO2C-,
(ix) (C1-C6-Alkoxy)carbonyl-,
(x) (C1-C6-Alkoxy)C(O)NH-,
(xi) (C1-C6-Akyl)amino-,
(xii) Di(C1-C6-alkyl)amino-,
(xiii) R10R11NC(O)-,
(xiv) R10O-,
(XV) R10R11N-,
(xvi) R10R11NS(O)2-,
(xvii) R10S(O)2NR11-,
(xviii) R10R11NC(O)NH-,
(xix) R10S-,
(XX) R10S(O)-,
(xxi) R10S(O)2-,
(xxii) R10C(O)-,
(xxiii) C1-C9-Heterocyclyl- optional substituiert mit C1-C6-Alkyl- oder C1-C6-Hydroxylalkyl-,
(xxiv) C1-C6-Hydroxylalkyl-,
(xxv) und Perfluor(C1-C6)alkyl-;
(e) C1-C6-Hydroxylalkyl-;
(f) C1-C9-Heterocyclyl-;
(g) C6-C14-Aryl-, optional substituiert mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus:
(i) C1-C6-Alkyl-, optional substituiert mit H2N-,
(ii) Heterocyclyl(C1-C6-alkyl)-,
(iii) Halogen,
(iv) Hydroxyl,
(v) H2N-,
(vi) O2N-,
(vii) H2NSO2-,
(viii) HO2C-,
(ix) (C1-C6-Alkoxy)carbonyl-,
(x) (C1-C6-Alkoxy)C(O)NH-,
(xi) (C1-C6-Akyl)amino-,
(xii) Di(C1-C6-alkyl)amino-,
(xiii) R10R11NC(O)-,
(xiv) R10O-,
(XV) R10R11N-,
(xvi) R10R11NS(O)2-,
(xvii) R10S(O)2NR11-,
(xviii) R10R11NC(O)NH-,
(xix) R10S-,
(XX) R10S(O)-,
(xxi) R10S(O)2-,
(xxii) R10C(O)-,
(xxiii) C1-C9-Heterocyclyl-, optional substituiert mit C1-C6-Alkyl- oder C1-C6-Hydroxylalkyl-,
(xxiv) C1-C6-Hydroxylalkyl-
(xxv) und Perfluor(C1-C6)alkyl-;
(h) oder C3-C8-Cycloalkyl-;
R10 und R11 unabhängig voneinander stehen für H, C1-C6-Alkoxy-, C1-C6-Alkyl-, C1-C6-Alkoxy(C2-C6-alkylen)-, (C1-C6-Alkyl)amino-C2-C6-alkylen-, Di(C1-C6-alkyl)amino-C2-C6-alkylen-, C2-C6-Alkenyl, C2-C6-Alkinyl, C6-C14-Aryl-, (C6-C14-Aryl)alkyl-, C3-C8-Cycloalkyl-, C1-C9-Heteroaryl-, (C1-C9-Heteroaryl)alkyl-, C1-C9-Heterocyclyl-, optional substituiert mit C1-C6-Alkyl-, oder Heterocyclyl(C1-C6-alkyl-);
oder R10 und R11 bilden, wenn sie zusammen mit dem Stickstoffatom genommen werden, an das sie gebunden sind, einen 3- bis 7-gliedrigen Heterocyclus, wobei bis zu zwei der Kohlenstoffatome des Heterocyclus optional ersetzt sind mit -N(H)-, -N(C1-C6-Alkyl)-, -N(C3-C8-Cycloalkyl)-, -N(C6-C14-Aryl)-, -N(C1-C9-Heteroaryl)-, -S-, -SO-, -S(O)2-, oder -O- und wobei jedes Kohlenstoffatom des Heterocyclus optional substituiert ist mit ein oder zwei Substituenten, die unabhängig voneinander ausgewählt sind aus C1-C6-Alkyl-, H2N-, (C1-C6-Alkyl)amino-, Di(C1-C6-Alkyl)amino-und C1-C9-Heterocyclyl-;
R7 und R8 unabhängig voneinander ausgewählt sind aus:
(a) H;
(b) C1-C6-Alkyl- optional substituiert mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus:
(i) C1-C8-Acyl-
(ii) C1-C6-Alkoxy-, optional substituiert mit -NH2,
(iii) (C1-C6-Alkoxy)carbonyl-,
(iv) H2N-,
(v) (C1-C6-Alkyl)amino-,
(vi) Di(C1-C6-alkyl)amino-,
(vii) (C1-C6-Alkyl)carboxyamido-, optional substituiert mit
A) H2N-,
B) (C1-C6-Alkyl)amino-,
C) oder Di(C1-C6-alkyl)amino-,
(viii) C6-C14-Aryl-,
(ix) C3-C8-Cycloalkyl-
(x) Halogen,
(xi) C1-C9-Heterocyclyl-, optional substituiert mit C1-C6-Alkyl-,
(xii) HO2C-,
(xiii) NC-,
(xiv) R10C(O)NR11-,
(xv) R10R11NC(O)-
(xvi) und C1-C9-Heteroaryl-;
(c) C1-C6-Alkoxy-;
(d) C1-C9-Heteroaryl-, optional substituiert mit 1 bis 3 Substituenten, unabhängig ausgewählt aus:
(i) C1-C6-Alkoxy-, optional substituiert mit
A) H2N-,
B) (C1-C6-Alkyl)amino-,
C) Di(C1-C6-alkyl)amino-,
D) C1-C9-Heterocyclyl-, optional substituiert mit C1-C6-Alkyl-
E) und Hydroxyl,
(ii) (C1-C6-Alkoxy)carbonyl-,
(iii) (C1-C6-Alkoxy)C(O)NH-,
(iv) C1-C6-Alkyl-, optional substituiert mit
A) H2N-,
B) (C1-C6-Alkyl)amino-,
C) oder Di(C1-C6-alkyl)amino-,
(v) (C1-C6-Alkyl)amino-,
(vi) Di(C1-C6-alkyl)amino-,
(vii) (C1-C6-Alkyl)amido-, optional substituiert mit
A) H2N-,
B) (C1-C6-Alkyl)amino-,
C) oder Di(C1-C6-alkyl)amino-
(viii) (C1-C6-Alkyl)carboxyamido-,
(ix) C1-C9-Heterocyclyl-, optional substituiert mit C1-C6-Alkyl- oder C1-C6-Hydroxylalkyl-,
(x) Heterocyclyl(C1-C6-alkyl)-, optional substituiert mit C1-C6-Alkyl-,
(xi) Halogen,
(xii) Hydroxyl,
(xiii) C1-C6-Hydroxylalkyl-,
(xiv) Perfluor(C1-C6)alkyl-,
(xv) H2N-,
(xvi) O2N-,
(xvii) H2NSO2-,
(xviii) HO2C-,
(xix) NC-,
(xx) R10R11NC(O)-,
(xxi) R10R11NNHC(O)-,
(xxii) R10O-,
(xxiii) R10R11N-,
(xxiv) R10R11NS(O)2-,
(xxv) R10S(O)2NR11-,
(xxvi) R10R11NC(O)NH-,
(xxvii) R10S-,
(xxviii) R10S(O)-,
(xxix) R10S(O)2-
(xxx) und R10C(O)-;
(e) C1-C6-Hydroxylalkyl-;
(f) C1-C9-Heterocyclyl-, optional substituiert mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus:
(i) C1-C6-Alkyl-,
(ii) Heterocyclyl(C1-C6-alkyl)-,
(iii) (C6-C14-Aryl)alkyl-,
(iv) C1-C8-Acyl-,
(v) (C1-C6-Alkoxy)carbonyl-,
(vi) (C1-C6-Alkyl)carboxyl-,
(vii) Halogen,
(viii) C1-C6-Haloalkyl-,
(ix) Hydroxyl,
(x) C1-C6-Hydroxyalkyl-,
(xi) H2N-,
(xii) (C1-C6-Alkyl)amino-,
(xiii) Di(C1-C6-alkyl)amino-,
(xiv) HO2C-,
(xv) (C1-C6-Alkoxy)carbonyl-,
(xvi) (C1-C6-Alkyl)carboxyl-,
(xvii) (C1-C6-Alkyl)amido-,
(xviii) H2NC(O)-,
(xix) (C1-C6-Alkyl)carboxyamido-
(xx) und -NO2;
(g) C6-C14-Aryl- optional substituiert mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus:
(i) C1-C6-Alkoxy-, optional substituiert mit
A) H2N-,
B) (C1-C6-Alkyl)amino-,
C) Di(C1-C6-alkyl)amino-,
D) C1-C9-Heterocyclyl-, optional substituiert mit C1-C6-Alkyl-
E) und Hydroxyl,
(ii) (C1-C6-Alkoxy)carbonyl-,
(iii) (C1-C6-Alkoxy)C(O)NH-,
(iv) C1-C6alkyl-, optional substituiert mit
A) H2N-,
B) (C1-C6-Alkyl)amino-
C) oder Di(C1-C6-alkyl)amino-,
(v) (C1-C6-Alkyl)amino-,
(vi) Di(C1-C6-alkyl)amino-,
(vii) (C1-C6-Alkyl)amido-, optional substituiert mit
A) H2N-,
B) (C1-C6-Alkyl)amino-
C) oder Di(C1-C6-alkyl)amino-,
(viii) (C1-C6-Alkyl)carboxyamido-,
(ix) C1-C9-Heterocyclyl-, optional substituiert mit C1-C6-Alkyl oder C1-C6-Hydroxylalkyl-,
(x) Heterocyclyl(C1-C6-alkyl)-, optional substituiert mit C1-C6-Alkyl-,
(xi) Halogen,
(xii) Hydroxyl,
(xiii) C1-C6-Hydroxylalkyl-,
(xiv) Perfluor(C1-C6)alkyl-,
(xv) H2N-,
(xvi) O2N-,
(xvii) H2NSO2-,
(xviii) HO2C-,
(xix) NC-,
(xx) R10R11NC(O)-,
(xxi) R10R11NNHC(O)-,
(xxii) R10O-,
(xxiii) R10R11N
(xxiv) R10R11NS(O)2-,
(xxv) R10S(O)2NR11-,
(xxvi) R10R11NC(O)NH-,
(xxvii) R10S-,
(xxviii) R10S(O)-,
(xxix) R10S(O)2-
(xxx) und R10C(O)-;
(h) und C3-C8-Cycloalkyl-, optional substituiert mit 1 bis 3 Substituenten, unabhängig voneinander ausgewählt aus:
(i) C1-C6-Alkyl-, optional substituiert mit Halogen,
(ii) (C1-C6-Alkoxy)carbonyl-,
(iii) (C1-C6-Alkyl)amido-,
(iv) (C1-C6-Alkyl)carboxyamido-,
(v) (C1-C6-Alkyl)carboxyl-,
(vi) C1-C6-Alkoxy-,
(vii) H2N-,
(viii) (C1-C6-Alkyl)amino-,
(ix) Di(C1-C6-alkyl)amino-,
(x) Hydroxyl,
(xi) H2NC(O)-,
(xii) HO2C-
(xiii) und -NO2;
wobei jede zwei Wasserstoffatome an demselben Kohlenstoffatom des C3-C8-Cycloalkyl-Rings ersetzt sein können durch ein Sauerstoffatom, um einen Oxo(=O)-Substituenten zu bilden,
und wobei jede zwei Wasserstoffatome an demselben Kohlenstoffatom des C3-C8-Cycloalkyl-Rings ersetzt sein können durch eine Alkylendioxy-Gruppe, so dass die Alkylendioxy-Gruppe, wenn sie zusammen mit dem Kohlenstoffatom genommen wird, an das sie gebunden ist, einen 5- bis 7-gliedrigen Heterocyclus bildet, der zwei Sauerstoffatome enthält;
oder R7 und R8, wenn sie zusammen genommen werden mit dem Stickstoffatom, an das sie gebunden sind, einen 3- bis 7-gliedrigen Heterocyclus bilden, wobei bis zu zwei der Kohlenstoffatome des Heterocyclus optional ersetzt sind durch -N(H)-, -N(C1-C6-Alkyl)-, -N(C6-C14-Aryl)-, -S-, -SO-, -S(O)2- oder -O-;
R9 für C1-C6-Alkyl-, C6-C14-Aryl-, (C6-C14-Aryl)alkyl- optional substituiert durch H2N-, C1-C9-Heterocyclyl- optional substituiert durch C1-C6-Alkyl-, C3-C8-Cycloalkyl-, C1-C6-Hydroxylalkyl-, oder C1-C6-Perfluoralkyl- steht;
R4 steht für:
a) Wasserstoff;
b) C1-C8-Acyl-;
c) C1-C6-Alkyl-;
d) H2N-, optional substituiert mit C1-C9-Heterocyclus,
e) (C1-C6-Alkyl)amino-, optional substituiert mit (C1-C6-Alkyl)SO2-,
f) Di(C1-C6-alkyl)amino-, optional substituiert mit (C1-C6-Alkyl)SO2-,
g) (C1-C6-Alkyl)amino-C1-C6-alkylen-,
h) Di(C1-C6-alkyl)amino-C1-C6-alkylen-,
i) Amino(C1-C6-alkyl)-;
j) C3-C8-Cycloalkyl-;
k) C6-C14-Aryl-, optional substituiert mit einem Substituenten, ausgewählt aus:
i) HO2C-,
ii) C1-C6-Hydroxylalkyl-,
iii) R12R13NC(O)-
iv) und (C1-C6-Alkoxy)carbonyl-;
l) C1-C9-Heterocyclus, optional substituiert mit C1-C6-Alkyl-;
m) (C1-C9-Heteroaryl)alkyl-;
n) Heterocyclyl(C1-C6-alkyl)-;
o) (C6-C14-Aryl)alkyl-;
p) Heterocyclyl(C1-C6-alkyl);
q) (C1-C9-Heteroaryl)alkyl-;
r) (C6-C14-Aryl)alkyl-;
s) C1-C6-Hydroxylalkyl-;
t) C1-C6-Perfluoralkyl-;
u) C1-C9-Heteroaryl-, optional substituiert mit einem Substituenten, ausgewählt aus:
i) HO2C-,
ii) C1-C6-Hydroxylalkyl-,
iii) R12R13NC(O)-
iv) und (C1-C6-Alkoxy)carbonyl-;
v) R3C(O)-N(R2)-Ar-;
w) R12R13NC(O)-;
x) R14OC(O)-
y) oder R14S(O)2-;
R5 steht für:
a) Wasserstoff;
b) C1-C8-Acyl-;
c) C1-C6-Alkyl-;
d) Amino(C1-C6-alkyl)-;
e) C3-C8-Cycloalkyl-;
f) C6-C14-Aryl-, optional substituiert mit einem Substituenten, ausgewählt aus:
i) HO2C-,
ii) C1-C6-Hydroxylalkyl-,
iii) R12R13NC(O)-
iv) und (C1-C6-Alkoxy)carbonyl-;
g) Halogen;
h) C1-C9-Heterocyclus, optional substituiert mit C1-C6-Alkyl-;
i) (C1-C9-Heteroaryl)alkyl-;
j) Heterocyclyl(C1-C6-alkyl)-;
k) (C6-C14-Aryl)alkyl-;
l) Heterocyclyl(C1-C6-alkyl);
m) (C1-C9-Heteroaryl)alkyl-;
n) (C6-C14-Aryl)alkyl-;
o) C1-C6-Hydroxylalkyl-;
p) C1-C6-Perfluoralkyl-;
q) C1-C9-Heteroaryl-, optional substituiert mit einem Substituenten, ausgewählt aus:
i) HO2C-,
ii) C1-C6-Hydroxylalkyl-,
iii) R12R13NC(O)-
iv) und (C1-C6-Alkoxy)carbonyl-;
r) R12R13NC(O)-;
s) R14OC(O)-
t) oder R14S(O)2-;
R12 und R13 unabhängig voneinander stehen für H, C1-C6-Alkyl-, C3-C8-Cycloalkyl-, C6-C14-Aryl-, C1-C9-Heteroaryl-, (C1-C9-Heteroaryl)alkyl-, Heterocyclyl(C1-C6-alkyl)-, (C6-C14-Aryl)alkyl- oder C1-C9-Heterocyclyl-, optional substituiert mit C1-C6-Alkyl-;
oder R12 und R13, wenn sie zusammengenommen werden mit dem Stickstoffatom, an das sie gebunden sind, einen 3- bis 7-gliedrigen Heterocyclus bilden, wobei bis zu zwei der Kohlenstoffatome des Heterocyclus optional ersetzt sind durch -N(H)-, -N(C1-C6-Alkyl)-, -N(C6-C14-Aryl)-, -S-, -SO-, -S(O)2- oder -O-;
R14 für C1-C6-Alkyl-, C6-C14-Aryl-, (C6-C14-Aryl)alkyl-, C1-C9-Heterocyclyl-, optional substituiert mit C1-C6-Alkyl-, C3-C8-Cycloalkyl-, C1-C6-Hydroxylalkyl- oder C1-C6-Perfluoralkyl-, steht.
1-{4-[4-(3,7-Dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phenyl}-3-pyridin-4-yl-harnstoff;
1-{4-[4-(3,7-Dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-harnstoff;
1-{4-[4-(3,7-Dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]-harnstoff;
1-{4-[2-(Dimethylamino)ethoxy]phenyl}-3-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phenyl}-harnstoff;
1-Methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}-harnstoff;
2-Hydroxyethyl{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}-carbamat;
1-[4-(4-Methylpiperazin-1-yl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}-harnstoff;
1-Ethyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}-harnstoff;
1-Cyclopropyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}-harnstoff;
1-{4-[4-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}-3-pyridin-4-yl-harnstoff;
1-[4-(Hydroxymethyl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}-harnstoff;
1-{4-[2-(Dimethylamino)ethoxy]phenyl}-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phenylpyrimidin-2-yl]phenyl}-harnstoff;
2-Hydroxyethyl{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}-carbamat;
1-Methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}-harnstoff;
1-{4-[4-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-yl-harnstoff;
1-[4-(4,6-Di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-3-methylharnstoff;
1-[4-(4,6-Di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-3-pyridin-4-yl-harnstoff;
1-[4-(4,6-Di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]-harnstoff;
1-[4-(4,6-Di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-1-ethyl-3-pyridin-4-yl-harnstoff;
1-[4-(4,6-Di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phenyl]-1-ethyl-3-[4-(4-methylpiperazin-1-yl)phenyl]-harnstoff;
Bis(2-hydroxyethyl){[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2,4-diyl]di-4,1-phenylen}-bis-carbamat;
N',N"'-{[6-(8-Oxa-3-azabicydo[3.2.1]oct-3-yl)pyrimidin-2,4-diyl]di-4,1-phenylen}-bis(1-methyl-harnstoff);
N',N"'-{[6-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2,4-diyl]di-4,1-phenylen}-bis(1-ethyl-harnstoff);
N',N"'-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2,4-diyl]di-4,1-phenylen}-bis(1-cyclopropyl-harnstoff);
N,N"-{[6-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2,4-diyl]di-4,1-phenylen}-bis(3-pyridin-3-yl-harnstoff);
N,N"-{[6-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2,4-diyl]di-4,1-phenylen}-bis(3-pyridin-4-yl-harnstoff);
N',N"'-{[6-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2,4-diyl]di-4,1-phenylen}-bis{1-[4-(4-methylpiperazin-1-yl)phenyl]-harnstoff}-;
4,4'-{[6-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2,4-diyl]bis(4,1-phenylencarbamoylimino)}-dibenzamid;
1-Methyl-3-{4-[4-(1-methylethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}-harnstoff;
1-Cyclopropyl-3-{4-[4-(1-methylethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}-harnstoff;
1-{4-[4-(1-Methylethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-yl-harnstoff;
1-{4-[4-(1-Methylethoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]-harnstoff;
1-Methyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}-phenyl)-harnstoff;
1-Cyclopropyl-3-(4-{4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}-phenyl)-harnstoff;
1-(4-{4-[(1-Methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}-phenyl)-3-pyridin-4-yl-harnstoff;
1-(4-{4-[(1-Methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}-phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]-harnstoff;
N~3~,N~3~-Dimethyl-N-(4-[(1-methylethyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-{4-[(pyridin-3-ylcarbamoyl)amino]phenyl}-pyrimidin-5-yl)-beta-alaninamid;
1-Methyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluormethyl)pyrimidin-2-yl]phenyl}-harnstoff;
1-Cyclopropyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluormethyl)pyrimidin-2-yl]phenyl}-harnstoff;
2-Hydroxyethyl{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluormethyl)pyrimidin-2-yl]phenyl}-carbamat;
1-{4-[4-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-trifluormethyl)pyrimidin-2-yl)phenyl}-3-pyridin-4-yl-harnstoff;
1-[4-(4-Methylpiperazin-1-yl)phenyl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1].1]oct-3-yl)-6-(trifluormethyl)pyrimidin-2-yl]phenyl}-harnstoff;
tert-Butylmethyl(4-{[(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}-phenyl)carbamoyl]amino}-benzyl)-carbamat;
1-Methyl-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}-phenyl)-harnstoff;
1-Ethyl-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}-phenyl)-harnstoff;
1-Cyclopropyl-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}-phenyl)-harnstoff;
1-(4-{4-[(Methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}-phenyl)-3-phenyl-harnstoff;
1-(4-{4-[(Methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}-phenyl)-3-pyridin-3-yl-harnstoff;
1-(4-{4-[(Methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}-phenyl)-3-pyridin-4-yl-harnstoff;
1-[4-(4-Methylpiperazin-1-yl)phenyl]-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}-phenyl)-harnstoff;
1-(4-{4-[(Methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}-phenyl)-3-(4-piperazin-1-ylphenyl)-harnstoff;
1-{4-[2-(Dimethylamino)ethoxy]phenyl}-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}-phenyl)-harnstoff;
1-{4-[(4-Methylpiperazin-1-yl)methyl]phenyl}-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}-phenyl)-harnstoff;
1-{4-[(Methylamino)methyl]phenyl}-3-(4-{4-[(methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}-phenyl)-harnstoff;
1-[4-(4,6-Di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-pyridin-4-yl-harnstoff;
1-{4-[2-(Dimethylamino)ethoxy]phenyl}-3-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-harnstoff;
1-[4-(4,6-Di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]-harnstoff;
1-[4-(4,6-Di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-harnstoff;
1-[4-(4,6-Di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-harnstoff;
1-{4-[4-(Isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-yl-harnstoff;
1-{4-[2-(Dimethylamino)ethoxy]phenyl}-3-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-harnstoff;
1-{4-[4-(Isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]-harnstoff;
1-{4-[4-(Isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-harnstoff;
1-{4-[4-(Isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-harnstoff;
1-[4-(4,6-Di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-pyridin-3-yl-harnstoff;
1-[4-(5-Chlor-4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-pyridin-3-yl-harnstoff;
1-[4-(5-Chlor-4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]-harnstoff;
1-{4-[4-(3-Oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}-3-pyridin-4-yl-harnstoff;
1-[4-(4-Methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}-harnstoff;
1-{4-[4-{[2-(Methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-pyridin-3-yl-harnstoff;
1-{4-[(4-Methylpiperazin-1-yl)methyl]phenyl}-3-(4-[4-([2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-harnstoff;
1-{4-[4-(3-Oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}-3-pyridin-3-yl-harnstoff;
1-{4-[2-(Dimethylamino)ethoxy]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}-harnstoff;
1-{4-[4-{[2-(Methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-yl-harnstoff;
1-{4-[2-(Dimethylamino)ethoxy]phenyl}-3-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-harnstoff;
1-[4-(4-Methylpiperazin-1-yl)phenyl]-3-{4-[4-{[2-(methylsulfonyl)ethyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-harnstoff;
1-{4-[(4-Methylpiperazin-1-yl)methyl)phenyl}-3-{4-[4-(3-oxa-8-azabicyclol[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phenyl}-harnstoff;
1-{4-[4-(Diethylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-yl-harnstoff;
1-{4-[4-(Diethylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phenyl}-3-[4-(4-methylpiperazin-1-yl)phenyl]-harnstoff;
1-(4-{4-[(1-Methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-3-[4-(pyrrolidin-1-ylmethyl)phenyl]-harnstoff;
1-(4-{4-[(1-Methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-3-pyridin-3-yl-harnstoff;
1-{4-[(Dimethylamino)methyl]phenyl}-3-(4-{4-[(1-methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-harnstoff;
1-(4-{4-[(1-Methylethyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-3-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-harnstoff;
1-(4-{4-[(Dimethylamino)methyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-3-pyridin-3-yl-harnstoff;
1-(4-{4-[(Dimethylamino)methyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-3-methyl-harnstoff;
1-(4-{4-[(Dimethylamino)methyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-3-ethyl-harnstoff;
1-(4-(4-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-cyclopropyl-harnstoff;
1-(4-(4-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-harnstoff;
1-(4-(4-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)-harnstoff;
1-(4-(4-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-(4-((dimethylamino)methyl)phenyl)-harnstoff;
1-(4-(4-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)phenyl)-3-phenyl-harnstoff;
1-{4-[4-(3-Oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}-3-pyridin-3-yl-harnstoff;
1-{4-[4-(3-Oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}-3-pyridin-4-yl-harnstoff;
1-[4-(4-Methylpiperazin-1-yl)phenyl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}-harnstoff;
1-[6-(4-Methylpiperazin-1-yl)pyridin-3-yl)-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}-harnstoff;
1-{4-[(4-Methylpiperazin-1-yl)carbonyl]phenyl}-3-(4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}-harnstoff;
1-(4-{[4-(1-Methylethyl)piperazin-1-yl]carbonyl}phenyl)-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}-harnstoff;
1-{4-[2-(Dimethylamino)ethoxy]phenyl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phenyl}-harnstoff;
1-(4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-3-pyridin-4-yl-harnstoff;
1-(4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]-harnstofif;
1-(4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-harnstoff;
1-(4-{4-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-3-pyridin-4-yl-harnstoff;
1-(4-{4-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]-harnstoff;
1-(4-{4-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-3-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-harnstoff;
1-(4-{4-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-harnstoff;
1-(4-{4-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-3-(4-{[4-(1-methylethyl)piperazin-1-yl]carbonyl}-phenyl)-harnstoff;
1-(4-{4-[(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-3-pyridin-4-yl-harnstoff;
1-[4-(4-Methylpiperazin-1-yl)phenyl]-3-(4-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-harnstoff;
1-{4-[(Dimethylamino)methyl]phenyl}-3-(4-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-harnstoff;
1-(4-{4-[(1R,4R)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-3-pyridin-4-yl-harnstoff;
1-[4-(4-Methylpiperazin-1-yl)phenyl]-3-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl)-phenyl)-harnstoff;
1-{4-[(4-Methylpiperazin-1-yl)methyl]phenyl}-3-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-harnstoff;
1-{4-[2-(Dimethylamino)ethoxy]phenyl}-3-(4-(4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-harnstoff;
1-(4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-3-pyridin-3-yl-harnstoff;
1-(4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-3-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}-harnstoff;
1-{4-[2-(Dimethylamino)ethoxy]phenyl}-3-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-harnstoff;
N,N-Dimethyl-4-{[(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)carbamoyl]amino}-benzamid;
1-(4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-3-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-harnstoff;
1-(4-{[4-(1-Methylethyl)piperazin-1-yl]carbonyl}-phenyl)-3-(4-{4-[(3R)-3-methylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phenyl)-harnstoff;
1-(4-{4-[(Dimethylamino)methyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}-phenyl)-3-methyl-harnstoff;
1-[4-(2,6-Di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phenyl]-3-methylharnstoff;
1-[4-(2,6-Di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phenyl]-3-pyridin-4-yl-harnstoff;
1-[4-(2,6-Di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phenyl]-3-[4-(4-methylpiperazin-1-yl)phenyl]-harnstoff;
1-Cyclopropyl-3-[4-(2,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phenyl]-harnstoff;
4-[4-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]anilin;
4-[4-Chlor-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]anilin;
4-[2-Chlor-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-4-yl]anilin;
8,8'-[2-(4-Nitrophenyl)pyrimidin-4,6-diyl]bis(3-oxa-8-azabicyclo[3.2.1]octan);
4-(4,6-Di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)anilin;
4-{4-[(Methylsulfonyl)methyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}-anilin;
4-(5-Chlor-4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)anilin;
9-(6-Chlor-2-(4-nitrophenyl)pyrimidin-4-yl)-3,7-dioxa-9-azabicyclo[3.3.1]nonan;
6-(3,7-Dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-N-isopropyl-2-(4-nitrophenyl)pyrimidin-4-amin;
2-(4-Aminophenyl)-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-N-isopropylpyrimidin-4-amin;
6-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(4-nitrophenyl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amin;
2-(4-Aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amin;
6-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(2-(methylsulfonyl)ethyl)-2-(4-nitrophenyl)pyrimidin-4-amin;
2-(4-Aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(2-(methylsulfonyl)ethyl)pyrimidin-4-amin;
6-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-N,N-diethyl-2-(4-nitrophenyl)pyrimidin-4-amin;
2-(4-Aminophenyl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N,N-diethylpyrimidin-4-amin;
4-(4-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((dimethylamino)methyl)pyrimidin-2-yl)anilin;
8-[6-(3,6-Dihydro-2H-pyran-4-yl)-2-(4-nitrophenyl)pyrimidin-4-yl]-3-oxa-8-azabicyclo[3.2.1]octan und
4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tetrahydro-2H-pyran-yl)pyrimidin-2-yl]anilin.
a) Synthetisieren einer Verbindung der Formel 68, wenn N(R2)H vorhanden ist:
durch Umsetzen einer Pyrimidin-Verbindung der Formel 66:
mit einer Dioxaborolan-2-yl-Verbindung 67:
um 68 zu ergeben, wobei die Variablen wie in Anspruch 1 definiert sind;
b) des Weiteren umfassend das Umsetzen von Verbindung 68 mit einem Acylierungsmittel
R3C(O)X, worin X eine Abgangsgruppe ist und worin R3 wie in Anspruch 1 definiert ist, um I zu ergeben:
oder ein pharmazeutisch annehmbares Salz davon.
(a) H ;
(b) (alkyle en C1-C6)- facultativement substitué par de 1 à 3 substituants indépendamment sélectionnés parmi :
(i) (alcoxy en C1-C6)-,
(ii) H2N-,
(iii) (alkyle en C1-C6)amino-,
(iv) di (alkyle en C1-C6)amino-,
(v) (aryle en C6-C14)-,
(vi) (hétérocyclyle en C1-C9)-facultativement substitué par (alkyle en C1-C6)-,
(vii) et (hétéroaryle en C1-C9)- ;
(c) (alcoxy en C1-C6)- ;
(d) (hétéroaryle en C1-C9)- facultativement substitué par de 1 à 3 substituants indépendamment sélectionnés parmi :
(i) (alkyle en C1-C6)- facultativement substitué par H2N-,
(ii) hétérocyclyl (alkyle en C1-C6)-,
(iii) halogéno,
(iv) hydroxyle,
(v) H2N-,
(vi) O2N-,
(vii) H2NSO2-,
(viii) HO2C-,
(ix) (alcoxy en C1-C6)carbonyl-,
(x) (alcoxy en C1-C6)C(O)NH-,
(xi) (alkyle en C1-C6)amino-,
(xii) di (alkyle en C1-C6)amino-,
(xiii) R10R11NC(O)-,
(xiv) R10O-,
(xv) R10R11N-,
(xvi) R10R11NS(O)2-,
(xvii) R10S(O)2NR11-,
(xviii) R10R11NC(O)NH-,
(xix) R10S-,
(xx) R10S(O)-,
(xxi) R10S(O)2-,
(xxii) R10C(O)-,
(xxiii) (hétérocyclyle en C1-C9)-facultativement substitué par (alkyle en C1-C6)-ou (hydroxylalkyle en C1-C6)-,
(xxiv) (hydroxylalkyle en C1-C6)-,
(xxv) et perfluoro (alkyle en C1-C6)- ;
(e) (hydroxylalkyle en C1-C6)- ;
(f) (hétérocyclyle en C1-C9)- ;
(g) (aryle en C6-C14)- facultativement substitué par de 1 à 3 substituants indépendamment sélectionnés parmi :
(i) (alkyle en C1-C6)- facultativement substitué par H2N-,
(ii) hétérocyclyl (alkyle en C1-C6)-,
(iii) halogéno,
(iv) hydroxyle,
(v) H2N-,
(vi) O2N-,
(vii) H2NSO2-,
(viii) HO2C-,
(ix) (alcoxy en C1-C6)carbonyl-,
(x) (alcoxy en C1-C6)C(O)NH-,
(xi) (alkyle en C1-C6)amino-,
(xii) di (alkyle en C1-C6)amino-,
(xiii) R10R11NC(O)-,
(xiv) R10O-,
(xv) R10R11N-,
(xvi) R10R11NS(O)2-,
(xvii) R10S(O)2NR11-,
(xviii) R10R11NC(O)NH-,
(xix) R10S-,
(xx) R10S(O)-,
(xxi) R10S(O)2-,
(xxii) R10C(O)-,
(xxiii) (hétérocyclyle en C1-C9)-facultativement substitué par (alkyle en C1-C6)-ou (hydroxylalkyle en C1-C6)-,
(xxiv) (hydroxylalkyle en C1-C6)-,
(xxv) et perfluoro (alkyle en C1-C6)- ;
(h) ou (cycloalkyle en C3-C8)- ;
R10 et R11 représentent chacun indépendamment H, (alcoxy en C1-C6)-, (alkyle en C1-C6)-, (alcoxy en C1-C6)(alkylène en C2-C6)-, (alkyle en C1-C6)amino-(alkylène en C2-C6)-, di (alkyle en C1-C6)amino-(alkylène en C2-C6)-, alkényle en C2-C6, alkynyle en C2-C6, (aryle en C6-C14)-, (aryle en C6-C14)alkyl-, (cycloalkyle en C3-C8)-, (hétéroaryle en C1-C9)-, (hétéroaryle en C1-C9)alkyl-, (hétérocyclyle en C1-C9)- facultativement substitué par (alkyle en C1-C6)-, ou hétérocyclyl (alkyle en C1-C6)- ;(a) H ;
(b) (alkyle en C1-C6)- facultativement substitué par de 1 à 3 substituants indépendamment sélectionnés parmi :
(i) (acyle en C1-C8)-
(ii) (alcoxy en C1-C6)- facultativement substitué par -NH2,
(iii) (alcoxy en C1-C6)carbonyl-,
(iv) H2N-,
(v) (alkyle en C1-C6)amino-,
(vi) di (alkyle en C1-C6)amino-,
(vii) (alkyle en C1-C6)carboxyamido-, facultativement substitué par
A) H2N-,
B) (alkyle en C1-C6)amino-,
C) ou di (alkyle en C1-C6)amino-,
(viii) (aryle en C6-C14)-,
(ix) (cycloalkyle en C3-C8)-
(x) halogéno,
(xi) (hétérocyclyle en C1-C9)-facultativement substitué par (alkyle en C1-C6)-,
(xii) HO2C-,
(xiii) NC-,
(xiv) R10C(O)NR11-,
(xv) R10R11NC(O)-,
(xvi) et (hétéroaryle en C1-C9)- ;
(c) (alcoxy en C1-C6)- ;
(d) (hétéroaryle en C1-C9)- facultativement substitué par de 1 à 3 substituants indépendamment sélectionnés parmi :
(i) (alcoxy en C1-C6)- facultativement substitué par
A) H2N-,
B) (alkyle en C1-C6)amino-,
C) di (alkyle en C1-C6)amino-,
D) (hétérocyclyle en C1-C9)-facultativement substitué par (alkyle en C1-C6)-,
E) et hydroxyle,
(ii) (alcoxy en C1-C6)carbonyl-,
(iii) (alcoxy en C1-C6)C(O)NH-,
(iv) (alkyle en C1-C6)- facultativement substitué par
A) H2N-,
B) (alkyle en C1-C6)amino-,
C) ou di (alkyle en C1-C6)amino-,
(v) (alkyle en C1-C6)amino-,
(vi) di (alkyle en C1-C6)amino-,
(vii) (alkyle en C1-C6)amido- facultativement substitué par
A) H2N-,
B) (alkyle en C1-C6)amino-,
C) ou di (alkyle en C1-C6)amino-,
(viii) (alkyle en C1-C6)carboxyamido-,
(ix) (hétérocyclyle en C1-C9)-facultativement substitué par (alkyle en C1-C6)-ou (hydroxylalkyle en C1-C6)-,
(x) hétérocyclyl (alkyle en C1-C6)-facultativement substitué par (alkyle en C1-C6)-,
(xi) halogéno,
(xii) hydroxyle,
(xiii) (hydroxylalkyle en C1-C6)-,
(xiv) perfluoro (alkyle en C1-C6)-,
(xv) H2N-,
(xvi) O2N-,
(xvii) H2NSO2-,
(xviii) HO2C-,
(xix) NC-,
(xx) R10R11NC(O)-,
(xxi) R10R11NNHC(O)-,
(xxii) R10O-,
(xxiii) R10R11N-,
(xxiv) R10R11NS(O)2-,
(xxv) R10S(O)2NR11-,
(xxvi) R10R11NC(O)NH-,
(xxvii) R10S-,
(xxviii) R10S(O)-,
(xxix) R10S(O)2-,
(xxx) et R10C(O)- ;
(e) (hydroxylalkyle en C1-C6)- ;
(f) (hétérocyclyle en C1-C9)- facultativement substitué par de 1 à 3 substituants indépendamment sélectionnés parmi :
(i) (alkyle en C1-C6)-,
(ii) hétérocyclyl (alkyle en C1-C6)-,
(iii) (aryle en C6-C14)alkyl-,
(iv) (acyle en C1-C8)-,
(v) (alcoxy en C1-C6)carbonyl-,
(vi) (alkyle en C1-C6)carboxyl-,
(vii) halogéno,
(viii) (halogénoalkyle en C1-C6)-,
(ix) hydroxyle,
(x) (hydroxyalkyle en C1-C6)-,
(xi) H2N-,
(xii) (alkyle en C1-C6)amino-,
(xiii) di (alkyle en C1-C6)amino-,
(xiv) HO2C-,
(xv) (alcoxy en C1-C6)carbonyl-,
(xvi) (alkyle en C1-C6)carboxyl-,
(xvii) (alkyle en C1-C6)amido-,
(xviii) H2NC(O)-,
(xix) (alkyle en C1-C6)carboxyamido-,
(xx) et -NO2 ;
(g) (aryle en C6-C14)- facultativement substitué par de 1 à 3 substituants indépendamment sélectionnés parmi :
(i) (alcoxy en C1-C6)- facultativement substitué par
A) H2N-,
B) (alkyle en C1-C6)amino-,
C) di (alkyle en C1-C6)amino-,
D) (hétérocyclyle en C1-C9)-facultativement substitué par (alkyle en C1-C6)-,
E) et hydroxyle,
(ii) (alcoxy en C1-C6)carbonyl-,
(iii) (alcoxy en C1-C6)C(O)NH-,
(iv) (alkyle en C1-C6)- facultativement substitué par
A) H2N-,
B) (alkyle en C1-C6)amino-,
C) ou di (alkyle en C1-C6)amino-,
(v) (alkyle en C1-C6)amino-,
(vi) di (alkyle en C1-C6)amino-,
(vii) (alkyle en C1-C6)amido- facultativement substitué par
A) H2N-,
B) (alkyle en C1-C6)amino-,
C) ou di (alkyle en C1-C6)amino-,
(viii) (alkyle en C1-C6)carboxyamido-,
(ix) (hétérocyclyle en C1-C9)- facultativement substitué par (alkyle en C1-C6)- ou (hydroxylalkyle en C1-C6)-,
(x) hétérocyclyl (alkyle en C1-C6)-facultativement substitué par (alkyle en C1-C6)-,
(xi) halogéno,
(xii) hydroxyle,
(xiii) (hydroxylalkyle en C1-C6)-,
(xiv) perfluoro(alkyle en C1-C6)-,
(xv) H2N-,
(xvi) O2N-,
(xvii) H2NSO2-,
(xviii) HO2C-,
(xix) NC-,
(xx) R10R11NC(O)-,
(xxi) R10R11NNHC(O)-,
(xxii) R10O-,
(xxiii) R10R11N-,
(xxiv) R10R11NS(O)2-,
(xxv) R10S(O)2NR11-,
(xxvi) R10R11NC(O)NH-,
(xxvii) R10S-,
(xxviii) R10S(O)-,
(xxix) R10S(O)2-,
(xxx) et R10C(O)- ;
(h) et (cycloalkyle en C3-C8)- facultativement substitué par de 1 à 3 substituants indépendamment sélectionnés parmi :
(i) (alkyle en C1-C6)- facultativement substitué par halogéno,
(ii) (alcoxy en C1-C6)carbonyl-,
(iii) (alkyle en C1-C6)amido-,
(iv) (alkyle en C1-C6)carboxyamido-,
(v) (alkyle en C1-C6)carboxyl-,
(vi) (alcoxy en C1-C6)-,
(vii) H2N-,
(viii) (alkyle en C1-C6)amino-,
(ix) di (alkyle en C1-C6)amino-,
(x) hydroxyle,
(xi) H2NC(O)-,
(xii) HO2C-,
(xiii) et -NO2 ;
deux atomes d'hydrogène quelconques sur le même atome de carbone du noyau (cycloalkyle en C3-C8)- pouvant être remplacés par un atome d'oxygène pour former un substituant oxo (=O),a) l'hydrogène ;
b) (acyle en C1-C8)- ;
c) (alkyle en C1-C6)- ;
d) H2N- facultativement substitué par un hétérocycle en C1-C9,
e) (alkyle en C1-C6)amino- facultativement substitué par (alkyle en C1-C6)SO2-,
f) di (alkyle en C1-C6)amino- facultativement substitué par (alkyle en C1-C6)SO2-,
g) (alkyle en C1-C6)amino-(alkylène en C1-C6)-,
h) di (alkyle en C1-C6)amino-(alkylène en C1-C6)-,
i) amino(alkyle en C1-C6)- ;
j) (cycloalkyle en C3-C8)- ;
k) (aryle en C6-C14)- facultativement substitué par un substituant sélectionné parmi :
i) HO2C-,
ii) (hydroxylalkyle en C1-C6)-,
iii) R12R13NC(O)-,
iv) et (alcoxy en C1-C6)carbonyl- ;
l) un hétérocycle en C1-C9 facultativement substitué par (alkyle en C1-C6)- ;
m) (hétéroaryle en C1-C9)alkyl- ;
n) hétérocyclyl (alkyle en C1-C6)- ;
o) (aryle en C6-C14)alkyl- ;
p) hétérocyclyl (alkyle en C1-C6) ;
q) (hétéroaryle en C1-C9)alkyl- ;
r) (aryle en C6-C14)alkyl- ;
s) (hydroxylalkyle en C1-C6)- ;
t) (perfluoroalkyle en C1-C6)- ;
u) (hétéroaryle en C1-C9)- facultativement substitué par un substituant sélectionné parmi :
i) HO2C-,
ii) (hydroxylalkyle en C1-C6)-,
iii) R12R13NC(O)-,
iv) et (alcoxy en C1-C6)carbonyl- ;
v) R3C(O)-N(R2)-Ar- ;
w) R12R13NC(O)- ;
x) R14OC(O)- ;
y) ou R14S(O)2- ;
R5 représente :a) l'hydrogène ;
b) (acyle en C1-C8)- ;
c) (alkyle en C1-C6)- ;
d) amino (alkyle en C1-C6)- ;
e) (cycloalkyle en C3-C8)- ;
f) (aryle en C6-C14)- facultativement substitué par un substituant sélectionné parmi :
i) HO2C-,
ii) (hydroxylalkyle en C1-C6)-,
iii) R12R13NC(O)-,
iv) et (alcoxy en C1-C6)carbonyl- ;
g) halogéno ;
h) un hétérocycle en C1-C9 facultativement substitué par (alkyle en C1-C6)- ;
i) (hétéroaryle en C1-C9)alkyl- ;
j) hétérocyclyl (alkyle en C1-C6)- ;
k) (aryle en C6-C14)alkyl- ;
l) hétérocyclyl (alkyle en C1-C6) ;
m) (hétéroaryle en C1-C9)alkyl- ;
n) (aryle en C6-C14)alkyl- ;
o) (hydroxylalkyle en C1-C6)- ;
p) (perfluoroalkyle en C1-C6)- ;
q) (hétéroaryle en C1-C9)- facultativement substitué par un substituant sélectionné parmi :
i) HO2C-,
ii) (hydroxylalkyle en C1-C6)-,
iii) R12R13NC(O)-,
iv) et (alcoxy en C1-C6)carbonyl- ;
r) R12R13NC(O)- ;
s) R14OC(O)- ;
t) ou R14S(O)2- ;
R12 et R13 représentent chacun indépendamment H, (alkyle en C1-C6)-, (cycloalkyle en C3-C8)-, (aryle en C6-C14)-, (hétéroaryle en C1-C9)-, (hétéroaryle en C1-C9)alkyl-, hétérocyclyl (alkyle en C1-C6)-, (aryle en C6-C14)alkyl- ou (hétérocyclyle en C1-C9)- facultativement substitué par (alkyle en C1-C6)- ;• la 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phényl}-3-pyridin-4-ylurée ;
• la 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phényl}-3-{4-[(4-méthylpipérazin-1-yl)méthyl]phényl}urée ;
• la 1-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)pyrimidin-2-yl]phényl}-3-[4-(4-méthylpipérazin-1-yl)phényl]urée ;
• la 1-{4-[2-(diméthylamino)éthoxy]phényl}-3-{4-[4-(3,7-dioxa-9-azabicyclo[3.3.1]non-9-yl)-6-(isopropylamino)-pyrimidin-2-yl]phényl}urée ;
• la 1-méthyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phénylpyrimidin-2-yl]phényl}urée ;
• le {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phénylpyrimidin-2-yl]phényl}carbamate de 2-hydroxyéthyle ;
• la 1-[4-(4-méthylpipérazin-1-yl)phényl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phénylpyrimidin-2-yl]phényl}urée ;
• la 1-éthyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phénylpyrimidin-2-yl]phényl}urée ;
• la 1-cyclopropyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phénylpyrimidin-2-yl]phényl}urée ;
• la 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phénylpyrimidin-2-yl]phényl}-3-pyridin-4-ylurée ;
• la 1-[4-(hydroxyméthyl)phényl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phénylpyrimidin-2-yl]phényl}urée ;
• la 1-{4-[2-(diméthylamino)éthoxy]phényl}-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-phénylpyrimidin-2-yl]phényl}urée ;
• le {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phényl}carbamate de 2-hydroxyéthyle ;
• la 1-méthyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phényl}urée ;
• la 1-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phényl}-3-pyridin-4-ylurée ;
• la 1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phényl]-3-méthylurée ;
• la 1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phényl]-3-pyridin-4-ylurée ;
• la 1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phényl]-3-[4-(4-méthylpipérazin-1-yl)phényl]urée ;
• la 1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phényl]-1-éthyl-3-pyridin-4-ylurée ;
• la 1-[4-(4,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-2-yl)phényl]-1-éthyl-3-[4-(4-méthylpipérazin-1-yl)phényl]urée ;
• le {[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phénylène}biscarbamate de bis(2-hydroxyéthyle) ;
• la N',N'"-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phénylène}bis(1-méthylurée) ;
• la N',N'"-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phénylène}bis(1-éthylurée) ;
• la N',N'"-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phénylène}bis(1-cyclopropylurée) ;
• la N,N"-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phénylène}bis(3-pyridin-3-ylurée) ;
• la N,N"-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-pyrimidine-2,4-diyl]di-4,1-phénylène}bis(3-pyridin-4-ylurée) ;
• la N',N"-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]di-4,1-phénylène}bis{1-[4-(4-méthylpipérazin-1-yl)phényl]urée} ;
• le 4,4'-{[6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidine-2,4-diyl]bis(4,1-phénylènecarbamoylimino)}-dibenzamide ;
• la 1-méthyl-3-{4-[4-(1-méthyléthoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phényl}urée ;
• la 1-cyclopropyl-3-{4-[4-(1-méthyléthoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phényl}urée ;
• la 1-{4-[4-(1-méthyléthoxy)-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]phényl}-3-pyridin-4-ylurée ;
• la 1-{4-[4-(1-méthyléthoxy)-6-(8-oxa-3-azabicyclo-[3.2.1]oct-3-yl)pyrimidin-2-yl]phényl}-3-[4-(4-méthylpipérazin-1-yl)phényl]urée ;
• la 1-méthyl-3-(4-{4-[(1-méthyléthyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phényl)urée ;
• la 1-cyclopropyl-3-(4-{4-[(1-méthyléthyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phényl)-urée ;
• la 1-(4-{4-[(1-méthyléthyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phényl)-3-pyridin-4-ylurée ;
• la 1-(4-{4-[(1-méthyléthyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phényl)-3-[4-(4-méthylpipérazin-1-yl)phényl]urée ;
• le N∼3∼,N∼3∼-diméthyl-N-(4-[(1-méthyléthyl)amino]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-2-{4-[(pyridin-3-ylcarbamoyl)amino]phényl}pyrimidin-5-yl)-bêta-alaninamide ;
• la 1-méthyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluorométhyl)pyrimidin-2-yl]phényl}urée ;
• la 1-cyclopropyl-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluorométhyl)pyrimidin-2-yl]phényl}urée ;
• le {4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluorométhyl)pyrimidin-2-yl]phényl}carbamate de 2-hydroxyéthyle ;
• la 1-{4-(4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluorométhyl)pyrimidin-2-yl)phényl}-3-pyridin-4-ylurée ;
• la 1-[4-(4-méthylpipérazin-1-yl)phényl]-3-{4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-6-(trifluorométhyl)pyrimidin-2-yl]phényl}urée ;
• le méthyl(4-{[(4-{4-[(méthylsulfonyl)méthyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phényl)-carbamoyl]amino}benzyl)carbamate de tert-butyle ;
• la 1-méthyl-3-(4-{4-[(méthylsulfonyl)méthyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phényl)urée ;
• la 1-éthyl-3-(4-{4-[(méthylsulfonyl)méthyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phényl)urée ;
• la 1-cyclopropyl-3-(4-{4-[(méthylsulfonyl)méthyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phényl)urée ;
• la 1-(4-{4-[(méthylsulfonyl)méthyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phényl)-3-phénylurée ;
• la 1-(4-{4-[(méthylsulfonyl)méthyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phényl)-3-pyridin-3-ylurée ;
• la 1-(4-{4-[(méthylsulfonyl)méthyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phényl)-3-pyridin-4-ylurée ;
• la 1-[4-(4-méthylpipérazin-1-yl)phényl]-3-(4-{4-[(méthylsulfonyl)méthyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phényl)urée ;
• la 1-(4-{4-[(méthylsulfonyl)méthyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phényl)-3-(4-pipérazin-1-ylphényl)urée ;
• la 1-{4-[2-(diméthylamino)éthoxy]phényl}-3-(4-{4-[(méthylsulfonyl)méthyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phényl)urée ;
• la 1-{4-[(4-méthylpipérazin-1-yl)méthyl]phényl}-3-(4-{4-[(méthylsulfonyl)méthyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phényl)urée ;
• la 1-{4-[(méthylamino)méthyl]phényl}-3-(4-{4-[(méthylsulfonyl)méthyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}phényl)urée ;
• la 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phényl]-3-pyridin-4-ylurée ;
• la 1-{4-[2-(diméthylamino)éthoxy]phényl}-3-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phényl]urée ;
• la 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phényl]-3-[4-(4-méthylpipérazin-1-yl)phényl]urée ;
• la 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phényl]-3-{4-[(4-méthylpipérazin-1-yl)méthyl]phényl}urée ;
• la 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phényl]-3-{4-[(4-méthylpipérazin-1-yl)carbonyl]phényl}urée ;
• la 1-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phényl}-3-pyridin-4-ylurée ;
• la 1-{4-[2-(diméthylamino)éthoxy]phényl}-3-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phényl}urée ;
• la 1-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phényl}-3-[4-(4-méthylpipérazin-1-yl)phényl]urée ;
• la 1-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phényl}-3-{4-[(4-méthylpipérazin-1-yl)méthyl]phényl}urée ;
• la 1-{4-[4-(isopropylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phényl}-3-[6-(4-méthylpipérazin-1-yl)pyridin-3-yl]urée ;
• la 1-[4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phényl]-3-pyridin-3-ylurée ;
• la 1-[4-(5-chloro-4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phényl]-3-pyridin-3-ylurée ;
• la 1-[4-(5-chloro-4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)phényl]-3-[4-(4-méthylpipérazin-1-yl)phényl]urée ;
• la 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tétrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phényl}-3-pyridin-4-ylurée ;
• la 1-[4-(4-méthylpipérazin-1-yl)phényl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tétrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phényl}urée ;
• la 1-{4-[4-{[2-(méthylsulfonyl)éthyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phényl}-3-pyridin-3-ylurée ;
• la 1-{4-[(4-méthylpipérazin-1-yl)méthyl]phényl}-3-{4-[4-{[2-(méthylsulfonyl)éthyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phényl}urée ;
• la 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tétrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phényl}-3-pyridin-3-ylurée ;
• la 1-{4-[2-(diméthylamino)éthoxy]phényl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tétrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phényl}urée ;
• la 1-{4-[4-{[2-(méthylsulfonyl)éthyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phényl}-3-pyridin-4-ylurée ;
• la 1-{4-[2-(diméthylamino)éthoxy]phényl}-3-{4-[4-{[2-(méthylsulfonyl)éthyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phényl}urée ;
• la 1-[4-(4-méthylpipérazin-1-yl)phényl]-3-{4-[4-{[2-(méthylsulfonyl)éthyl]amino}-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phényl}urée ;
• la 1-{4-[(4-méthylpipérazin-1-yl)méthyl)phényl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tétrahydro-2H-pyran-4-ylamino)pyrimidin-2-yl]phényl}urée ;
• la 1-{4-[4-(diéthylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phényl}-3-pyridin-4-ylurée ;
• la 1-{4-[4-(diéthylamino)-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl]phényl}-3-[4-(4-méthylpipérazin-1-yl)phényl]urée ;
• la 1-(4-{4-[(1-méthyléthyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)-3-[4-(pyrrolidin-1-ylméthyl)phényl]urée ;
• la 1-(4-{4-[(1-méthyléthyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)-3-pyridin-3-ylurée ;
• la 1-{4-[(diméthylamino)méthyl]phényl}-3-(4-{4-[(1-méthyléthyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)urée ;
• la 1-(4-{4-[(1-méthyléthyl)amino]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)-3-[4-(2-pyrrolidin-1-yléthoxy)phényl]urée ;
• la 1-(4-{4-[(diméthylamino)méthyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)-3-pyridin-3-ylurée ;
• la 1-(4-{4-[(diméthylamino)méthyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)-3-méthylurée ;
• la 1-(4-{4-[(diméthylamino)méthyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)-3-éthylurée ;
• la 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((diméthylamino)méthyl)pyrimidin-2-yl)phényl)-3-cyclopropylurée ;
• la 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((diméthylamino)méthyl)pyrimidin-2-yl)phényl)-3-(4-(4-méthylpipérazin-1-yl)phényl)urée ;
• la 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((diméthylamino)méthyl)pyrimidin-2-yl)phényl)-3-(4-(2-(diméthylamino)éthoxy)phényl)urée ;
• la 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((diméthylamino)méthyl)pyrimidin-2-yl)phényl)-3-(4-((diméthylamino)méthyl)phényl)urée ;
• la 1-(4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((diméthylamino)méthyl)pyrimidin-2-yl)phényl)-3-phénylurée ;
• la 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tétrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phényl}-3-pyridin-3-ylurée ;
• la 1-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tétrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phényl}-3-pyridin-4-ylurée ;
• la 1-[4-(4-méthylpipérazin-1-yl)phényl]-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tétrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phényl}urée ;
• la 1-[6-(4-méthylpipérazin-1-yl)pyridin-3-yl)-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tétrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phényl}urée ;
• la 1-{4-[(4-méthylpipérazin-1-yl)carbonyl]phényl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tétrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phényl}urée ;
• la 1-(4-{[4-(1-méthyléthyl)pipérazin-1-yl)carbonyl)phényl)-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tétrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phényl}urée ;
• la 1-{4-[2-(diméthylamino)éthoxy]phényl}-3-{4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tétrahydro-2H-pyran-4-yl)pyrimidin-2-yl]phényl}urée ;
• la 1-(4-{4-[(3R)-3-méthylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)-3-pyridin-4-ylurée ;
• la 1-(4-{4-[(3R)-3-méthylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)-3-[4-(4-méthylpipérazin-1-yl)phényl]urée ;
• la 1-(4-{4-[(3R)-3-méthylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)-3-[6-(4-méthylpipérazin-1-yl)pyridin-3-yl]urée ;
• la 1-(4-{4-[(2R,6S)-2,6-diméthylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)-3-pyridin-4-ylurée ;
• la 1-(4-{4-[(2R,6S)-2,6-diméthylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)-3-[4-(4-méthylpipérazin-1-yl)phényl]urée ;
• la 1-(4-{4-[(2R,6S)-2,6-diméthylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)-3-[6-(4-méthylpipérazin-1-yl)pyridin-3-yl]urée ;
• la 1-(4-{4-[(2R,6S)-2,6-diméthylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)-3-{4-[(4-méthylpipérazin-1-yl)carbonyl]phényl}urée ;
• la 1-(4-{4-[(2R,6S)-2,6-diméthylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)-3-(4-{[4-(1-méthyléthyl)pipérazin-1-yl]carbonyl}phényl)urée ;
• la 1-(4-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)-3-pyridin-4-ylurée ;
• la 1-[4-(4-méthylpipérazin-1-yl)phényl]-3-(4-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)urée ;
• la 1-{4-[(diméthylamino)méthyl]phényl}-3-(4-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)urée ;
• la 1-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)-3-pyridin-4-ylurée ;
• la 1-[4-(4-méthylpipérazin-1-yl)phényl]-3-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)urée ;
• la 1-{4-[(4-méthylpipérazin-1-yl)méthyl]phényl}-3-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)urée ;
• la 1-{4-[2-(diméthylamino)éthoxy]phényl}-3-(4-{4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)urée ;
• la 1-(4-{4-[(3R)-3-méthylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)-3-pyridin-3-ylurée ;
• la 1-(4-{4-[(3R)-3-méthylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)-3-{4-[(4-méthylpipérazin-1-yl)méthyl]phényl}urée ;
• la 1-{4-[2-(diméthylamino)éthoxy]phényl}-3-(4-{4-[(3R)-3-méthylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)urée ;
• le N,N-diméthyl-4-{[(4-{4-[(3R)-3-méthylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)carbamoyl]amino}benzamide ;
• la 1-(4-{4-[(3R)-3-méthylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)-3-{4-[(4-méthylpipérazin-1-yl)carbonyl]phényl}urée ;
• la 1-(4-{[4-(1-méthyléthyl)pipérazin-1-yl]carbonyl}phényl)-3-(4-{4-[(3R)-3-méthylmorpholin-4-yl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)urée ;
• la 1-(4-{4-[(diméthylamino)méthyl]-6-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)pyrimidin-2-yl}phényl)-3-méthylurée ;
• la 1-[4-(2,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phényl]-3-méthylurée ;
• la 1-[4-(2,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phényl]-3-pyridin-4-ylurée ;
• la 1-[4-(2,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phényl]-3-[4-(4-méthylpipérazin-1-yl)phényl]urée ;
• la 1-cyclopropyl-3-[4-(2,6-di-8-oxa-3-azabicyclo[3.2.1]oct-3-ylpyrimidin-4-yl)phényl]urée ;
• la 4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]aniline ;
• la 4-[4-chloro-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]aniline ;
• la 4-[2-chloro-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-4-yl]aniline ;
• le 8,8'-[2-(4-nitrophényl)pyrimidine-4,6-diyl]bis(3-oxa-8-azabicyclo[3.2.1]octane) ;
• la 4-(4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)aniline ;
• la 4-{4-[(méthylsulfonyl)méthyl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl}aniline ;
• la 4-(5-chloro-4,6-di-3-oxa-8-azabicyclo[3.2.1]oct-8-ylpyrimidin-2-yl)aniline ;
• le 9-(6-chloro-2-(4-nitrophényl)pyrimidin-4-yl)-3,7-dioxa-9-azabicyclo[3.3.1]nonane ;
• la 6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-N-isopropyl-2-(4-nitrophényl)pyrimidin-4-amine ;
• la 2-(4-aminophényl)-6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-N-isopropylpyrimidin-4-amine ;
• la 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-2-(4-nitrophényl)-N-(tétrahydro-2H-pyran-4-yl)pyrimidin-4-amine ;
• la 2-(4-aminophényl)-6-(3-oxa-8-azabicyclo[3.2.1]-octan-8-yl)-N-(tétrahydro-2H-pyran-4-yl)pyrimidin-4-amine ;
• la 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(2-(méthylsulfonyl)éthyl)-2-(4-nitrophényl)pyrimidin-4-amine ;
• la 2-(4-aminophényl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(2-(méthylsulfonyl)éthyl)pyrimidin-4-amine ;
• la 6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N,N-diéthyl-2-(4-nitrophényl)pyrimidin-4-amine ;
• la 2-(4-aminophényl)-6-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-N,N-diéthylpyrimidin-4-amine ;
• la 4-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-((diméthylamino)méthyl)pyrimidin-2-yl)aniline ;
• le 8-[6-(3,6-dihydro-2H-pyran-4-yl)-2-(4-nitrophényl)pyrimidin-4-yl]-3-oxa-8-azabicyclo[3.2.1]octane ; et
• la 4-[4-(3-oxa-8-azabicyclo[3.2.1]oct-8-yl)-6-(tétrahydro-2H-pyran-4-yl)pyrimidin-2-yl]aniline.
a) la synthèse d'un composé de Formule 68 lorsque N(R2)H est présent :
par réaction d'un composé pyrimidine de formule 66 :
avec un composé dioxaborolan-2-yle 67 :
pour obtenir 68, les variables étant telles que définies dans la revendication 1 ;
b) et comprenant en outre la réaction d'un composé 68 avec un agent acylant R3C(O)X, dans lequel X est un groupe partant et R3 est tel que défini dans la revendication 1, pour obtenir I :
ou un sel pharmaceutiquement acceptable de celui-ci.
REFERENCES CITED IN THE DESCRIPTION
Patent documents cited in the description
Non-patent literature cited in the description